Cycloalkyl substituted triazole compounds as agonists of the apj receptor

ABSTRACT

Compounds of Formula I and Formula II, pharmaceutically acceptable salt thereof, stereoisomers of any of the foregoing, or mixtures thereof are agonists of the APJ Receptor and may have use in treating cardiovascular and other conditions. Compounds of Formula I and Formula II have the following structures: (I) (II) where the definitions of the variables are provided herein.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/422,901, filed on Nov. 16, 2016, which is hereby incorporated byreference in its entirety and for all purposes as if fully set forthherein.

FIELD OF THE INVENTION

The present invention relates to compounds capable of acting as agonistsof the APJ Receptor, and compositions that include compounds that areagonists of the APJ Receptor. The compounds and compositions may be usedto activate the APJ Receptor and to treat various disease conditions. Anexample of one area where such compounds may be used is in the treatmentof cardiovascular conditions. In particular, the compounds may be usedto improve contractility and ejection fraction in subjects with chronicheart failure and may be used to treat patients with heart failure withreduced ejection fraction and patients with heart failure with preservedejection fraction.

BACKGROUND OF THE INVENTION

Apelin is the endogenous ligand for APJ (APLNR, angiotensin receptorlike-1). The APJ receptor is a member of the rhodopsin-like Gprotein-coupled receptor (GPCR) family. The apelin/APJ system has beenobserved in many tissues such as heart, kidney, pancreas, lung and thecentral nervous system. This suggests diverse roles of the system in thephysiology and pathology of mammals.

Apelin peptides are processed from a 77 residue pre-pro form intosmaller bioactive fragments, mainly a 36 residue form (Apelin 42-77—alsoreferred to as Apelin-36) and a smaller 13 residue polypeptide (Apelin65-77—also referred to as Apelin-13) Hosoya et al., J. Biol. Chem.275:21061-21067, 2000. Apelin peptides were previously determined to beendogenous ligands for the orphan APJ receptor, a member of the seventransmembrane G-protein-coupled receptor superfamily. Tatemoto et al.,Biochem. Biophysi. Res. Commun. 251:471-476, 1998. One of the shortermore active isoforms identified, pyroglutamated apelin-13([PE65]Apelin-13 (65-77), has been reported to be the most potent andabundant form of apelin in cardiac tissue. Maguire et al., Hypertension54:598-604, 2009. In vitro and preclinical models have suggested thatthe apelin/APJ system has a role in cardiovascular homeostasis as wellas metabolism. Barnes et al., Heart 96:1011-1016, 2010. Circulatingapelin levels are transient and Apelin-13 has a brief plasma half-lifeof <5 min leading to short-lived cardiovascular effects.

In vitro, exogenous apelin increases contractility at subnanomolarconcentrations in atrial strips and whole rat hearts, and increasessarcomere shortening by up to 140% in isolated cardiomyocyctes. Barneset al., Heart 96:1011-1016, 2010. Apelin also has a potent inotropiceffect in an ex vivo isolated heart assay. In vivo, acute apelininfusion restores ejection fraction, increases cardiac output andreduces left ventricular end-diastolic pressure in rats with chronicheart failure. Berry et al., Circulation 110:187-193, 2004. Exogenousapelin potently enhances myocardial contractility without inducing leftventricular hypertrophy concomitant with reduction in ventricularpreload and afterload. Barnes et al., Heart 96:1011-1016, 2010.

Studies from Kawamata et al and Hosoya et al have shown that thatshorter peptide apelin-13 had approximately a 3.5-fold higher in vitroaffinity to the APJ receptor than apelin-36. Kawamata et al., BBA 1538:162-171, 2001, Hosoya et al., JBC 275: 21061-21067. Apelin-13 analogueswere reported having a single substitution with either canonical ornon-canonical amino acids. The authors also reported double and triplesubstitutions in apelin 66-77 and apelin 63-77, but not in apelin-13.The emphasis was on peptides reported to have higher in vitro affinityand potency than apelin-13. Nishizawa et al., in: T. Shioiri (ed.),Peptide Science 2000: Proceedings of the₃₇th Japanese Peptide Symposium,pp. 151-154. Several if not all of these modified peptides are reportedin later studies. U.S. Pat. No. 7,635,751.

In a 2003 study (Medhurst et al., J. Neurochemistry 84:1162-1172, 2003)in vitro activity of apelin-36, apelin-17 and apelin-13 was compared. Itwas concluded that all three peptides were approximately equipotent.C-terminal amidation resulted in about a 14-fold decrease in affinity. Amore recent study (Hamada et al., J. Mol. Med. 22:547-552, 2008)reported cyclic analogues of apelin-13. When tested for in vitroactivity all three analogues maintained function activity, although withreduced potency relative to apelin-13.

A shortened 12 amino acid-apelin peptide having ligand activity on APJwas reported in a 2009 patent (U.S. Pat. No. 7,635,751). The peptidecould have a substitution of one non-canonical amino acid. In anotherapplication, WO 2013/111110 A2 and U.S. Pat. No. 8,673,848, cyclicmimetics of apelin have also been reported.

Another study reported synthesizing analogs of apelin-13 with amino acidsubstitutions with non-canonical amino acids at the C-terminal end ofthe molecule, but no pegylation at the N- or C-terminus or another sitespecific location. The use of internal PEG spacers (short PEG (n=4 or6), however, was also reported in lower activity peptide analogs withdeletions in the middle of the sequence that contained fewer amino acidresidues than apelin-13. Murza et al. ChemMedChem 7:318-325, 2012.Additionally, PCT/US2013/075773 describes a group of modifications,including substitution of non-canonical amino acids and changes at theN- and C-terminal of the apelin molecule that can affect, inter alia,the potency of the molecule. The increased potency can be a result ofincreased half-life or decreased degradation relative to wild-typeapelin.

Despite the advancements that have been made with respect to peptides, aneed exists for small molecule agonists of the APJ receptor. However,some progress has been made in this area. For example, WO 2014/044738discloses various benzimidazole-carboxylic acid amide derivatives asmodulators of the APJ Receptor. Other small molecule agonists of the APJreceptor are disclosed in U.S. Pat. Appl. Pub. No. US 2016/0340336, WO2016/187308, WO 2015/184011, and WO 2015/188073.

A need continues to exist for agonists of the APJ receptor that may beused to treat various cardiovascular and other conditions. The presentapplication discloses such agonists of the APJ receptor s that may besuitable for use as therapeutic agents in treating a variety ofconditions. These compounds may find particular benefit in treatingcardiovascular conditions. For example, such compounds may be beneficialin treating conditions such as chronic systolic heart failure andchronic diastolic heart failure.

SUMMARY OF THE INVENTION

In one aspect, the invention provides a compound of Formula I or FormulaII:

or a pharmaceutically acceptable salt thereof, a tautomer thereof, apharmaceutically acceptable salt of the tautomer, a stereoisomer of anyof the foregoing, or a mixture thereof,wherein:

R¹ is an unsubstituted monocyclic C₃-C₈ cycloalkyl, an unsubstitutedC₅-C₈ polycyclic cycloalkyl, an unsubstituted monocyclic C₄-C₈cycloalkenyl, a monocyclic C₃-C₈ cycloalkyl substituted with 1, 2, 3, or4 R^(1a) substituents, a C₅-C₈ polycyclic cycloalkyl substituted with 1,2, or 3 R^(1a) substituents, or a monocyclic C₄-C₈ cycloalkenylsubstituted with 1, 2, or 3 R^(1a) substituents;

R^(1a) in each instance is independently selected from —F, —Cl, —Br, —I,—CN, —OH, ═O, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆perhaloalkyl), —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl,—C₂-C₄ alkenyl, ═CH₂, ═CH—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-OH, —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)-OH, —(C₁-C₆haloalkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ perhaloalkyl)-OH, —(C₁-C₆perhaloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,—C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂,—C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —NHS(═O)₂—(C₁-C₆ alkyl),—S(═O)₂—(C₁-C₆ alkyl), a phenyl group, or a monocyclic heteroaryl groupwith 5 or 6 ring members containing 1, 2, or 3 heteroatoms independentlyselected from N, O, or S, wherein the R^(1a) phenyl and R^(1a)heteroaryl groups are unsubstituted or are substituted with 1, 2, or 3,R^(1a′) substituents; and further wherein two R^(1a) groups on a singlecarbon atom of a monocyclic C₃-C₈ cycloalkyl R¹ group may join togetherwith the carbon atom to which they are attached to form a heterocyclicring having 3 to 6 members of which 1 or 2 are heteroatoms independentlyselected from O, N, and S;

R^(1a′) is in each instance, independently selected from —F, —Cl, —Br,—I, —CN, —OH, O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆perhaloalkyl), —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl,—C₂-C₄ alkenyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl),—(C₁-C₆ haloalkyl)-OH, —(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆perhaloalkyl)-OH, —(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂,—NHS(═O)₂—(C₁-C₆ alkyl), or —S(═O)₂—(C₁-C₆ alkyl);

R² is selected from —H, or C₁-C₄ alkyl or is absent in the compounds ofFormula II;

R³ is selected from a group of formula —(CR^(3b)R^(3c))-Q, a group offormula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q, a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—C(═O)-Q, a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—CH(OH)-Q, a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3f))—(CR^(3f)R^(3g))-Q a group of formula—(C₃-C₈ cycloalkyl)-Q, or a group of formula -(heterocyclyl)-Q, whereinthe heterocyclyl of the -(heterocyclyl)-Q group has 5 to 7 ring membersof which 1, 2, or 3 are heteroatoms independently selected from N, O, orS and is unsubstituted or is substituted with 1, 2, or 3 R^(3h)substituents, and further wherein the C₃-C₈ cycloalkyl of the —(C₃-C₈cycloalkyl)-Q group is unsubstituted or is substituted with 1 or 2R^(3h) substituents;

R^(3b) and R^(3c) are independently selected from —H, —F, —Cl, —CN,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or—N(C₁-C₆ alkyl)₂;

R^(3d) and R^(3e) are independently selected from —H, —F, —Cl, —CN,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-O—(C₁-C₆alkyl)-phenyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl),—NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;

R^(3f) and R^(3g) are independently selected from —H, —F, —Cl, —CN,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₂-C₆ alkenyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or—N(C₁-C₆ alkyl)₂;

R^(3h) in each instance is independently selected from —F, —Cl, —CN,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)—(C₃-C₆ cycloalkyl),—C(═O)—O—(C₁-C₆ alkyl), oxo, or —C(═O)-(heterocyclyl), wherein theheterocyclyl group of the R^(h)—C(═O)-(heterocyclyl) has 5 or 6 ringmembers of which 1 or 2 are heteroatoms independently selected from N,or S or has 3 or 4 ring members of which 1 is a heteroatom selected fromN, O, or S;

Q is a monocyclic or bicyclic C₆-C₁₀ aryl group, a monocyclic orbicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or3 heteroatoms independently selected from N, O, or S, a C₃-C₈ cycloalkylgroup, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3heteroatoms independently selected from N, O, or S, wherein the C₆-C₁₀aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups areunsubstituted or are substituted with 1, 2, 3, or 4 R^(Q) substituents;and further wherein the Q heterocyclyl group may additionally besubstituted with 1 or 2 oxo substituents, and the Q heteroaryl group mayinclude an N-oxide if the heteroaryl includes a N heteroatom;

R^(Q) in each instance is independently selected from —F, —Cl, —Br, —I,—CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —C₂-C₆alkenyl, —C₂-C₆ alkynyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl),—O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,—NHC(═O)(C₁-C₆ alkyl), —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂,—S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆alkyl), —(C₁-C₆ alkyl)-NH₂, —(C₁-C₆ alkyl)-NH—(C₁-C₆ alkyl), —(C₁-C₆alkyl)-N—(C₁-C₆ alkyl)₂, phenyl, a heterocyclyl group, a —(C₁-C₆alkyl)heterocyclyl group, or a heteroaryl group with 5 or 6 ring membersand 1, 2, or 3, heteroatoms independently selected from N, O, or S,wherein the heterocyclyl groups of the R^(Q) heterocyclyl and —(C₁-C₆alkyl)heterocyclyl groups have 3 to 6 ring members of which 1 or 2 areheteroatoms independently selected from N, O, or S, and further whereinthe heterocyclyl and the heterocyclyl of the —(C₁-C₆ alkyl)heterocyclylR^(Q) groups may be further substituted with one or two oxo substituentsand a substituent selected from —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₆alkyl, or —C(═O)—(C₁-C₆ alkyl);

R⁴ is selected from a monocyclic or bicyclic C₆-C₀ aryl group, amonocyclic or bicyclic heteroaryl group with 5 to 10 ring memberscontaining 1, 2, or 3 heteroatoms independently selected from N, O, orS, a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring memberscontaining 1, 2, 3, or 4 heteroatoms independently selected from N, O,or S, a monocyclic 3-6 membered cycloalkyl group, or a straight orbranched chain C₁-C₆ alkyl group, wherein the C₆-C₁ aryl, theheteroaryl, the heterocyclyl, and the cycloalkyl R⁴ group areunsubstituted or are substituted with 1, 2, 3, or 4 R^(4a) substituents,and further wherein the straight or branched chain C₁-C₆ alkyl R⁴ groupis unsubstituted or is substituted with 1, 2, or 3 R^(4b) substituents;

R^(4a) in each instance is independently selected from —F, —Cl, —Br, —I,—CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —OH, —O—(C₁-C₆ alkyl),—O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆ alkyl-OH)₂, —C(═O)—(C₁-C₆alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆alkyl), —C(═O)N(C₁-C₆ alkyl)₂, phenyl, —S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆alkyl)-heterocyclyl, or heterocyclyl wherein the heterocyclyl of the—(C₁-C₆ alkyl)-heterocyclyl and heterocyclyl R^(4a) groups is a 3-6membered ring comprising 1 or 2 heteroatoms independently selected fromN, O, or S, and is unsaturated or partially unsaturated and isoptionally substituted with 1 or 2 oxo substituents, and further whereinthe heterocyclyl of the R⁴ group may be further substituted with 1 oxosubstituent; and

R^(4b) in each instance is selected from —F, —Cl, —Br, —I, —CN, —OH,—O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂,—NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆alkyl-OH)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl),—C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, or,—S(═O)₂—(C₁-C₆ alkyl);

wherein if R¹ is an unsubstituted cyclopropyl, if R⁴ is an unsubstitutedcyclopropyl group, or if R⁴ is a substituted or unsubstituted straightor branched chain C₁-C₆ alkyl group, then at least one of the followingis true:

-   -   (a) if R⁴ is an unsubstituted cyclopropyl group, then R³ is a        group of formula -(heterocyclyl)-Q or R³ is a group of formula        —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q and at least one of R^(3d),        R^(3e), R^(3f), or R^(3g) is not —H;    -   (b) if R¹ is an unsubstituted cyclopropyl, then R⁴ is a        substituted or unsubstituted monocyclic or bicyclic C₆-C₀ aryl        group, a substituted or unsubstituted monocyclic or bicyclic        heteroaryl group with 5 to 10 ring members containing 1, 2, or 3        heteroatoms independently selected from N, O, or S, or is a        substituted or unsubstituted monocyclic or bicyclic heterocyclyl        group with 5 to 10 ring members containing 1, 2, 3, or 4        heteroatoms independently selected from N, O, or S, a monocyclic        3-6 membered cycloalkyl group; or    -   (c) if R⁴ is a substituted or unsubstituted straight or branched        chain C₁-C₆ alkyl group, then R³ is a group of formula        -(heterocyclyl)-Q or R³ is a group of formula        —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q and at least one of R^(3d),        R^(3e), R^(3f), or R^(3g) is not —H.

Numerous other embodiments of the compound of Formula I and Formula IIare set forth herein.

Also provided are pharmaceutical compositions that include at least onepharmaceutically acceptable excipient, carrier or diluent and thecompound or the pharmaceutically acceptable salt thereof, the tautomerthereof, the pharmaceutically acceptable salt of the tautomer, thestereoisomer of any of the foregoing, or the mixture thereof accordingto any one of the embodiments.

In other embodiments, the invention provides a method of treating acardiovascular condition. Such methods typically include administeringto a subject an effective amount of the compound or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof according to any one of theembodiments or a pharmaceutical composition of any of the embodiments.In some such embodiments, the cardiovascular condition is heart failure.In some such embodiments, the cardiovascular condition is heart failurewith reduced ejection fraction whereas in other embodiments it is heartfailure with preserved ejection fraction. Thus, in some embodiments, thecardiovascular condition is chronic systolic heart failure or chronicdiastolic heart failure. In other embodiments, the cardiovascularcondition is acute heart failure whereas in other embodiments, thecardiovascular condition is hypertension.

In still other embodiments, the invention provides a method of improvingcardiac contractility in a subject. Such methods typically includeadministering to the subject an effective amount of the compound or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof according to any one of theembodiments or a pharmaceutical composition of any of the embodiments.

In still other embodiments, the invention provides a method ofincreasing ejection fraction in a subject suffering from acardiovascular condition. Such methods typically include administeringto the subject an effective amount of the compound or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof according to any one of theembodiments or a pharmaceutical composition of any of the embodiments.In such embodiments, the ejection fraction is increased in the subjectafter administration.

In still other embodiments, the invention provides a method of treatinga condition in a subject where it is desired to activate the APJReceptor. Such methods typically include administering to the subject aneffective amount of the compound or the pharmaceutically acceptable saltthereof, the tautomer thereof, the pharmaceutically acceptable salt ofthe tautomer, the stereoisomer of any of the foregoing, or the mixturethereof according to any one of the embodiments or a pharmaceuticalcomposition of any of the embodiments. In some such embodiments, thecondition is obesity or diabetes whereas in other such embodiments, thecondition is diabetic nephropathy or chronic kidney disease.

In other embodiments, the invention provides the compound or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof according to any one of theembodiments or a pharmaceutical composition of any of the embodimentsfor use in treating a cardiovascular condition. In some suchembodiments, the cardiovascular condition is heart failure. In some suchembodiments, the cardiovascular condition is heart failure with reducedejection fraction whereas in other embodiments it is heart failure withpreserved ejection fraction. Thus, in some embodiments, thecardiovascular condition is chronic systolic heart failure or chronicdiastolic heart failure. In other embodiments, the cardiovascularcondition is acute heart failure whereas in other embodiments, thecardiovascular condition is hypertension.

In still other embodiments, the invention provides the compound or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof according to any one of theembodiments or a pharmaceutical composition of any of the embodimentsfor improving the cardiac contractility in a subject suffering from acardiovascular condition.

In still other embodiments, the invention provides the compound or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof according to any one of theembodiments or a pharmaceutical composition of any of the embodimentsfor improving the ejection fraction in a subject suffering from acardiovascular condition.

In still other embodiments, the invention provides the compound or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof according to any one of theembodiments or a pharmaceutical composition of any of the embodimentsfor treating a condition in a subject where it is desired to activatethe APJ Receptor. In some such embodiments, the condition is obesity ordiabetes whereas in other such embodiments, the condition is diabeticnephropathy or chronic kidney disease.

Other objects, features and advantages of the invention will becomeapparent to those skilled in the art from the following description andclaims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph plotting different concentrations of angiotensin(AngII) with fixed concentration of pyr apelin-13 added to the humanAPJ-AT1R (angiotensin Type 1) double stable CHO cell line. The functionof the inositol phosphate accumulation (IP1) was measured byTime-resolved fluorescence resonance energy (TR-FRET) at 620 nm and 665nm respectively. Addition of pyr apelin-13 induces the positivecooperativity on the AT1R upon activation by APJ receptor.

FIG. 2 is a graph plotting different concentrations of angiotensin(AngII) with fixed concentration of pyr apelin-13 added to the human APJreceptor expressed in the CHO cell line. The function of the inositolphosphate accumulation (IP1) was measured by Time-resolved fluorescenceresonance energy (TR-FRET) at 620 nm and 665 nm respectively. There wasno positive cooperativity observed upon treatment with pyr apelin-13when the human APJ receptor is expressed alone.

FIG. 3 is a graph plotting different concentrations of angiotensin(AngII) with fixed concentration of pyr apelin-13 added to the humanAT1R receptor expressed in the CHO cell line. The function of theinositol phosphate accumulation (IP1) was measured by Time-resolvedfluorescence resonance energy (TR-FRET) at 620 nm and 665 nmrespectively. There was no positive cooperativity observed when thehuman AT1R receptor is expressed alone by pyr apelin-13 in the absenceof APJ expression.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, and so forth used in the specificationand claims are to be understood as being modified in all instances bythe term “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in the following specification andattached claims are approximations that may vary depending upon thestandard deviation found in their respective testing measurements.

As used herein, if any variable occurs more than one time in a chemicalformula, its definition on each occurrence is independent of itsdefinition at every other occurrence. If the chemical structure andchemical name conflict, the chemical structure is determinative of theidentity of the compound. The compounds of the present disclosure maycontain one or more chiral centers and/or double bonds and therefore,may exist as stereoisomers, such as double-bond isomers (i.e., geometricisomers), enantiomers or diastereomers. Accordingly, any chemicalstructures within the scope of the specification depicted, in whole orin part, with a relative configuration encompass all possibleenantiomers and stereoisomers of the illustrated compounds including thestereoisomerically pure form (e.g., geometrically pure, enantiomericallypure or diastereomerically pure) and enantiomeric and stereoisomericmixtures. Enantiomeric and stereoisomeric mixtures can be resolved intothe component enantiomers or stereoisomers using separation techniquesor chiral synthesis techniques well known to the skilled artisan.

The term “comprising” is meant to be open ended, i.e., all encompassingand non-limiting. It may be used herein synonymously with “having” or“including”. Comprising is intended to include each and every indicatedor recited component or element(s) while not excluding any othercomponents or elements. For example, if a composition is said tocomprise A and B. This means that the composition has A and B in it, butmay also include C or even C, D, E, and other additional components.

Certain compounds of the invention may possess asymmetric carbon atoms(optical centers) or double bonds; the racemates, enantiomers,diastereomers, geometric isomers and individual isomers are all intendedto be encompassed within the scope of the invention. Furthermore,atropisomers and mixtures thereof such as those resulting fromrestricted rotation about two aromatic or heteroaromatic rings bonded toone another are intended to be encompassed within the scope of theinvention. For example, when R⁴ is a phenyl group and is substitutedwith two groups bonded to the C atoms adjacent to the point ofattachment to the N atom of the triazole, then rotation of the phenylmay be restricted. In some instances, the barrier of rotation is highenough that the different atropisomers may be separated and isolated.

As used herein and unless otherwise indicated, the term “stereoisomer”or “stereomerically pure” means one stereoisomer of a compound that issubstantially free of other stereoisomers of that compound. For example,a stereomerically pure compound having one chiral center will besubstantially free of the mirror image enantiomer of the compound. Astereomerically pure compound having two chiral centers will besubstantially free of other diastereomers of the compound. A typicalstereomerically pure compound comprises greater than about 80% by weightof one stereoisomer of the compound and less than about 20% by weight ofother stereoisomers of the compound, more preferably greater than about90% by weight of one stereoisomer of the compound and less than about10% by weight of the other stereoisomers of the compound, even morepreferably greater than about 95% by weight of one stereoisomer of thecompound and less than about 5% by weight of the other stereoisomers ofthe compound, and most preferably greater than about 97% by weight ofone stereoisomer of the compound and less than about 3% by weight of theother stereoisomers of the compound. If the stereochemistry of astructure or a portion of a structure is not indicated with, forexample, bold or dashed lines, the structure or portion of the structureis to be interpreted as encompassing all stereoisomers of it. A bonddrawn with a wavy line indicates that both stereoisomers areencompassed. This is not to be confused with a wavy line drawnperpendicular to a bond which indicates the point of attachment of agroup to the rest of the molecule.

As described above, this invention encompasses the use ofstereomerically pure forms of such compounds, as well as the use ofmixtures of those forms. For example, mixtures comprising equal orunequal amounts of the enantiomers of a particular compound of theinvention may be used in methods and compositions of the invention.These isomers may be asymmetrically synthesized or resolved usingstandard techniques such as chiral columns or chiral resolving agents.See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions(Wiley-Interscience, New York, 1981); Wilen, S. H., et al. (1997)Tetrahedron 33:2725; Eliel, E. L., Stereochemistry of Carbon Compounds(McGraw-Hill, N Y, 1962); and Wilen, S. H., Tables of Resolving Agentsand Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre DamePress, Notre Dame, Ind., 1972).

As known by those skilled in the art, certain compounds of the inventionmay exist in one or more tautomeric forms. Because one chemicalstructure may only be used to represent one tautomeric form, it will beunderstood that for convenience, referral to a compound of a givenstructural formula includes tautomers of the structure represented bythe structural formula.

As noted above, compounds of the invention may exist in multipletautomeric forms. This is particularly true in compounds of Formula Iwhere R² is H. These forms are illustrated below as Tautomer A andTautomer B:

Compounds of the invention are depicted structurally and named ascompounds in the “Tautomer A” form. However, it is specificallycontemplated and known that the compounds exist in “Tautomer B” form andthus compounds in “Tautomer B” form are expressly considered to be partof the invention. For this reason, the claims refer to compounds ofFormula I and Formula II. Depending on the compound, some compounds mayexist primarily in one form more than another. Also, depending on thecompound and the energy required to convert one tautomer to the other,some compounds may exist as mixtures at room temperature whereas othersmay be isolated in one tautomeric form or the other. Examples of othertautomers associated with compounds of the invention are those with apyridone group (a pyridinyl) for which hydroxypyridine is a tautomer andcompounds with a ketone group with the enol tautomer. Examples of theseare shown below.

Compounds of the present disclosure include, but are not limited to,compounds of Formula I and Formula II and all pharmaceuticallyacceptable forms thereof. Pharmaceutically acceptable forms of thecompounds recited herein include pharmaceutically acceptable salts,solvates, crystal forms (including polymorphs and clathrates), chelates,non-covalent complexes, prodrugs, and mixtures thereof. In certainembodiments, the compounds described herein are in the form ofpharmaceutically acceptable salts. As used herein, the term “compound”encompasses not only the compound itself, but also a pharmaceuticallyacceptable salt thereof, a solvate thereof, a chelate thereof, anon-covalent complex thereof, a prodrug thereof, and mixtures of any ofthe foregoing. In some embodiments, the term “compound” encompasses thecompound itself, pharmaceutically acceptable salts thereof, tautomers ofthe compound, pharmaceutically acceptable salts of the tautomers, andester prodrugs such as (C₁-C₄)alkyl esters. In other embodiments, theterm “compound” encompasses the compound itself, pharmaceuticallyacceptable salts thereof, tautomers of the compound, pharmaceuticallyacceptable salts of the tautomers.

The term “solvate” refers to the compound formed by the interaction of asolvent and a compound. Suitable solvates are pharmaceuticallyacceptable solvates, such as hydrates, including monohydrates andhemi-hydrates.

The compounds of the invention may also contain naturally occurring orunnatural proportions of atomic isotopes at one or more of the atomsthat constitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). Radiolabeled compounds areuseful as therapeutic or prophylactic agents, research reagents, e.g.,assay reagents, and diagnostic agents, e.g., in vivo imaging agents. Allisotopic variations of the compounds of the invention, whetherradioactive or not, are intended to be encompassed within the scope ofthe invention. For example, if a variable is said or shown to be H, thismeans that variable may also be deuterium (D) or tritium (T).

“Alkyl” refers to a saturated branched or straight-chain monovalenthydrocarbon group derived by the removal of one hydrogen atom from asingle carbon atom of a parent alkane. Typical alkyl groups include, butare not limited to, methyl, ethyl, propyls such as propan-1-yl andpropan-2-yl, butyls such as butan-1-yl, butan-2-yl,2-methyl-propan-1-yl, 2-methyl-propan-2-yl, tert-butyl, and the like. Incertain embodiments, an alkyl group comprises 1 to 20 carbon atoms. Insome embodiments, alkyl groups include 1 to 10 carbon atoms or 1 to 6carbon atoms whereas in other embodiments, alkyl groups include 1 to 4carbon atoms. In still other embodiments, an alkyl group includes 1 or 2carbon atoms. Branched chain alkyl groups include at least 3 carbonatoms and typically include 3 to 7, or in some embodiments, 3 to 6carbon atoms. An alkyl group having 1 to 6 carbon atoms may be referredto as a (C₁-C₆)alkyl group and an alkyl group having 1 to 4 carbon atomsmay be referred to as a (C₁-C₄)alkyl. This nomenclature may also be usedfor alkyl groups with differing numbers of carbon atoms. The term “alkylmay also be used when an alkyl group is a substituent that is furthersubstituted in which case a bond between a second hydrogen atom and a Catom of the alkyl substituent is replaced with a bond to another atomsuch as, but not limited to, a halogen, or an O, N, or S atom. Forexample, a group —O—(C₁-C₆ alkyl)-OH will be recognized as a group wherean —O atom is bonded to a C₁-C₆ alkyl group and one of the H atomsbonded to a C atom of the C₁-C₆ alkyl group is replaced with a bond tothe O atom of an —OH group. As another example, a group —O—(C₁-C₆alkyl)-O—(C₁-C₆ alkyl) will be recognized as a group where an —O atom isbonded to a first C₁-C₆ alkyl group and one of the H atoms bonded to a Catom of the first C₁-C₆ alkyl group is replaced with a bond to a secondO atom that is bonded to a second C₁-C₆ alkyl group.

“Alkenyl” refers to an unsaturated branched or straight-chainhydrocarbon group having at least one carbon-carbon double bond derivedby the removal of one hydrogen atom from a single carbon atom of aparent alkene. The group may be in either the Z- or E-form (cis ortrans) about the double bond(s). Typical alkenyl groups include, but arenot limited to, ethenyl; propenyls such as prop-1-en-1-yl,prop-1-en-2-yl, prop-2-en-1-yl (allyl), and prop-2-en-2-yl; butenylssuch as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, andbuta-1,3-dien-2-yl; and the like. In certain embodiments, an alkenylgroup has 2 to 20 carbon atoms and in other embodiments, has 2 to 6carbon atoms. An alkenyl group having 2 to 6 carbon atoms may bereferred to as a (C₂-C₆)alkenyl group.

“Alkynyl” refers to an unsaturated branched or straight-chainhydrocarbon having at least one carbon-carbon triple bond derived by theremoval of one hydrogen atom from a single carbon atom of a parentalkyne. Typical alkynyl groups include, but are not limited to, ethynyl;propynyl; butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and thelike. In certain embodiments, an alkynyl group has 2 to 20 carbon atomsand in other embodiments, has 2 to 6 carbon atoms. An alkynyl grouphaving 2 to 6 carbon atoms may be referred to as a —(C₂-C₆)alkynylgroup.

“Alkoxy” refers to a radical —OR where R represents an alkyl group asdefined herein. Representative examples include, but are not limited to,methoxy, ethoxy, propoxy, butoxy, and the like. Typical alkoxy groupsinclude 1 to 10 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atomsin the R group. Alkoxy groups that include 1 to 6 carbon atoms may bedesignated as —O—(C₁-C₆) alkyl or as —O—(C₁-C₆ alkyl) groups. In someembodiments, an alkoxy group may include 1 to 4 carbon atoms and may bedesignated as —O—(C₁-C₄) alkyl or as —O—(C₁-C₄ alkyl) groups group.

“Aryl” refers to a monovalent aromatic hydrocarbon group derived by theremoval of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Aryl encompasses monocyclic carbocyclic aromaticrings, for example, benzene. Aryl also encompasses bicyclic carbocyclicaromatic ring systems where each of the rings is aromatic, for example,naphthalene. Aryl groups may thus include fused ring systems where eachring is a carbocyclic aromatic ring. In certain embodiments, an arylgroup includes 6 to 10 carbon atoms. Such groups may be referred to asC₆-C₁₀ aryl groups. Aryl, however, does not encompass or overlap in anyway with heteroaryl as separately defined below. Hence, if one or morecarbocyclic aromatic rings is fused with an aromatic ring that includesat least one heteroatom, the resulting ring system is a heteroarylgroup, not an aryl group, as defined herein.

“Carbonyl” refers to the radical —C(O) which may also be referred to as—C(═O) group.

“Carboxy” refers to the radical —C(O)OH which may also be referred to as—C(═O)OH.

“Cyano” refers to the radical —CN.

“Cycloalkyl” refers to a saturated cyclic alkyl group derived by theremoval of one hydrogen atom from a single carbon atom of a parentcycloalkane. Typical cycloalkyl groups include, but are not limited to,groups derived from cyclopropane, cyclobutane, cyclopentane,cyclohexane, cycloheptane, cyclooctane, and the like. Cycloalkyl groupsmay be described by the number of carbon atoms in the ring. For example,a cycloalkyl group having 3 to 8 ring members may be referred to as a(C₃-C₈)cycloalkyl, a cycloalkyl group having 3 to 7 ring members may bereferred to as a (C₃-C₇)cycloalkyl and a cycloalkyl group having 4 to 7ring members may be referred to as a (C₄-C₇)cycloalkyl. In certainembodiments, the cycloalkyl group can be a (C₃-C₁₀)cycloalkyl, a(C₃-C₈)cycloalkyl, a (C₃-C₇)cycloalkyl, a (C₃-C₆)cycloalkyl, or a(C₄-C₇)cycloalkyl group and these may be referred to as C₃-C₁₀cycloalkyl, C₃-C₈ cycloalkyl, C₃-C₇ cycloalkyl, C₃-C₆ cycloalkyl, orC₄-C₇ cycloalkyl groups using alternative language. Cycloalkyl groupsmay be monocyclic or polycyclic. For the purposes of this application,the term “polycyclic” when used with respect to cycloalkyl will includebicyclic cycloalkyl groups such as, but not limited to, norbornane,bicyclo[1.1.1]pentane, and bicyclo[3.1.0]hexane, and cycloalkyl groupswith more ring systems such as, but not limited to, cubane. The term“polycyclic” when used with respect to cycloalkyl will also includespirocyclic ring systems such as, but not limited to, spiro[2.2]pentane,spiro[2.3]hexane, spiro[3.3]heptane, and spiro[3.4]octane.

“Heterocyclyl” and “heterocyclic” refer to a cyclic group that includesat least one saturated, partially unsaturated, but non-aromatic, cyclicring. Heterocyclyl groups include at least one heteroatom as a ringmember. Typical heteroatoms include, O, S and N and are independentlychosen. Heterocyclyl groups include monocyclic ring systems and bicyclicring systems. Bicyclic heterocyclyl groups include at least onenon-aromatic ring with at least one heteroatom ring member that may befused to a cycloalkyl ring or may be fused to an aromatic ring where thearomatic ring may be carbocyclic or may include one or more heteroatoms.The point of attachment of a bicyclic heterocyclyl group may be at thenon-aromatic cyclic ring that includes at least one heteroatom or atanother ring of the heterocyclyl group. For example, a heterocyclylgroup derived by removal of a hydrogen atom from one of the 9 memberedheterocyclic compounds shown below may be attached to the rest of themolecule at the 5-membered ring or at the 6-membered ring.

In some embodiments, a heterocyclyl group includes 5 to 10 ring membersof which 1, 2, 3 or 4 or 1, 2, or 3 are heteroatoms independentlyselected from O, S, or N. In other embodiments, a heterocyclyl groupincludes 3 to 7 ring members of which 1, 2, or 3 heteroatom areindependently selected from O, S, or N. In such 3-7 memberedheterocyclyl groups, only 1 of the ring atoms is a heteroatom when thering includes only 3 members and includes 1 or 2 heteroatoms when thering includes 4 members. In some embodiments, a heterocyclyl groupincludes 3 or 4 ring members of which 1 is a heteroatom selected from O,S, or N. In other embodiments, a heterocyclyl group includes 5 to 7 ringmembers of which 1, 2, or 3 are heteroatoms independently selected fromO, S, or N. Typical heterocyclyl groups include, but are not limited to,groups derived from epoxides, aziridine, azetidine, imidazolidine,morpholine, piperazine, piperidine, hexahydropyrimidine,1,4,5,6-tetrahydropyrimidine, pyrazolidine, pyrrolidine, quinuclidine,tetrahydrofuran, tetrahydropyran, benzimidazolone, pyridinone, and thelike. Heterocyclyl groups may be fully saturated, but may also includeone or more double bonds. Examples of such heterocyclyl groups include,but are not limited to, 1,2,3,6-tetrahydropyridinyl,3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-pyranyl, 2,5-dihydro-1H-pyrolyl,2,3-dihydro-1H-pyrolyl, 1H-azirinyl, 1,2-dihydroazetenyl, and the like.Substituted heterocyclyl also includes ring systems substituted with oneor more oxo (═O) or oxide (—O—) substituents, such as piperidinylN-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, pyridinonyl,benzimidazolonyl, benzo[d]oxazol-2(3H)-only,3,4-dihydroisoquinolin-1(2H)-only, indolin-only,1H-imidazo[4,5-c]pyridin-2(3H)-only, 7H-purin-8(9H)-only,imidazolidin-2-only, 1H-imidazol-2(3H)-only,1,1-dioxo-1-thiomorpholinyl, and the like. In heterocyclyl groupcontaining a sulfur atom, the sulfur atom may be bonded to 0, 1, or 2 Oatoms in addition to the adjacent ring members such that the sulfur mayin various oxidation states. For example, a saturated 5-memberedheterocycle containing one heteroatom which is a S may include thefollowing heterocycles.

“Disease” refers to any disease, disorder, condition, symptom, orindication.

“Halo” or “halogen” refers to a fluoro, chloro, bromo, or iodo group.

“Haloalkyl” refers to an alkyl group in which at least one hydrogen isreplaced with a halogen. Thus, the term “haloalkyl” includesmonohaloalkyl (alkyl substituted with one halogen atom) andpolyhaloalkyl (alkyl substituted with two or more halogen atoms).Representative “haloalkyl” groups include difluoromethyl,2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like. The term“perhaloalkyl” means, unless otherwise stated, an alkyl group in whicheach of the hydrogen atoms is replaced with a halogen atom. For example,the term “perhaloalkyl”, includes, but is not limited to,trifluoromethyl, pentachloroethyl,1,1,1-trifluoro-2-bromo-2-chloroethyl, and the like.

“Heteroaryl” refers to a monovalent heteroaromatic group derived by theremoval of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Heteroaryl groups typically include 5- to14-membered, but more typically include 5- to 10-membered aromatic,monocyclic, bicyclic, and tricyclic rings containing one or more, forexample, 1, 2, 3, or 4, or in certain embodiments, 1, 2, or 3,heteroatoms chosen from O, S, or N, with the remaining ring atoms beingcarbon. In monocyclic heteroaryl groups, the single ring is aromatic andincludes at least one heteroatom. In some embodiments, a monocyclicheteroaryl group may include 5 or 6 ring members and may include 1, 2,3, or 4 heteroatoms, 1, 2, or 3 heteroatoms, 1 or 2 heteroatoms, or 1heteroatom where the heteroatom(s) are independently selected from O, S,or N. In bicyclic aromatic rings, both rings are aromatic. In bicyclicheteroaryl groups, at least one of the rings must include a heteroatom,but it is not necessary that both rings include a heteroatom although itis permitted for them to do so. For example, the term “heteroaryl”includes a 5- to 7-membered heteroaromatic ring fused to a carbocyclicaromatic ring or fused to another heteroaromatic ring. In tricyclicaromatic rings, all three of the rings are aromatic and at least one ofthe rings includes at least one heteroatom. For fused, bicyclic andtricyclic heteroaryl ring systems where only one of the rings containsone or more heteroatoms, the point of attachment may be at the ringincluding at least one heteroatom or at a carbocyclic ring. When thetotal number of S and O atoms in the heteroaryl group exceeds 1, thoseheteroatoms are not adjacent to one another. In certain embodiments, thetotal number of S and O atoms in the heteroaryl group is not more than2. In certain embodiments, the total number of S and O atoms in thearomatic heterocycle is not more than 1. Heteroaryl does not encompassor overlap with aryl as defined above. Examples of heteroaryl groupsinclude, but are not limited to, groups derived from acridine,carbazole, cinnoline, furan, imidazole, indazole, indole, indolizine,isobenzofuran, isochromene, isoindole, isoquinoline, isothiazole,2H-benzo[d][1,2,3]triazole, isoxazole, naphthyridine, oxadiazole,oxazole, perimidine, phenanthridine, phenanthroline, phenazine,phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine,pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline,quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene,triazole, and the like. In certain embodiments, the heteroaryl group canbe between 5 to 20 membered heteroaryl, such as, for example, a 5 to 14membered or 5 to 10 membered heteroaryl. In certain embodiments,heteroaryl groups can be those derived from thiophene, pyrrole,benzothiophene, 2H-benzo[d][1,2,3]triazole benzofuran, indole, pyridine,quinoline, imidazole, benzimidazole, oxazole, tetrazole, and pyrazine.

“Pharmaceutically acceptable” refers to generally recognized for use inanimals, and more particularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound thatis pharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, and the like; or (2) salts formed when an acidicproton present in the parent compound either is replaced by a metal ion,e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; orcoordinates with an organic base such as ethanolamine, diethanolamine,triethanolamine, N-methylglucamine, dicyclohexylamine, and the like.

“Pharmaceutically acceptable excipient” refers to a broad range ofingredients that may be combined with a compound or salt of the presentinvention to prepare a pharmaceutical composition or formulation.Typically, excipients include, but are not limited to, diluents,colorants, vehicles, anti-adherents, glidants, disintegrants, flavoringagents, coatings, binders, sweeteners, lubricants, sorbents,preservatives, and the like.

“Stereoisomer” refers to an isomer that differs in the arrangement ofthe constituent atoms in space. Stereoisomers that are mirror images ofeach other and optically active are termed “enantiomers,” andstereoisomers that are not mirror images of one another and areoptically active are termed “diastereomers.”

“Subject” includes mammals and humans. The terms “human” and “subject”are used interchangeably herein.

“Therapeutically effective amount” refers to the amount of a compoundthat, when administered to a subject for treating a disease, or at leastone of the clinical symptoms of a disease or disorder, is sufficient toaffect such treatment for the disease, disorder, or symptom. As thoseskilled in the art will recognize this amount is typically not limitedto a single dose, but may comprise multiple dosages over a significantperiod of time as required to bring about a therapeutic or prophylacticresponse in the subject. Thus, a “therapeutically effective amount” isnot limited to the amount in a single capsule or tablet, but may includemore than one capsule or tablet, which is the dose prescribed by aqualified physician or medical care provider. The “therapeuticallyeffective amount” can vary depending on the compound, the disease,disorder, and/or symptoms of the disease or disorder, severity of thedisease, disorder, and/or symptoms of the disease or disorder, the ageof the subject to be treated, and/or the weight of the subject to betreated. An appropriate amount in any given instance can be readilyapparent to those skilled in the art or capable of determination byroutine experimentation.

“Treating” or “treatment” of any disease or disorder refers to arrestingor ameliorating a disease, disorder, or at least one of the clinicalsymptoms of a disease or disorder, reducing the risk of acquiring adisease, disorder, or at least one of the clinical symptoms of a diseaseor disorder, reducing the development of a disease, disorder or at leastone of the clinical symptoms of the disease or disorder, or reducing therisk of developing a disease or disorder or at least one of the clinicalsymptoms of a disease or disorder. “Treating” or “treatment” also refersto inhibiting the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both, or inhibiting at leastone physical parameter which may not be discernible to the subject.Further, “treating” or “treatment” refers to delaying the onset of thedisease or disorder or at least symptoms thereof in a subject which maybe exposed to or predisposed to a disease or disorder even though thatsubject does not yet experience or display symptoms of the disease ordisorder.

Reference will now be made in detail to embodiments of the presentdisclosure. While certain embodiments of the present disclosure will bedescribed, it will be understood that it is not intended to limit theembodiments of the present disclosure to those described embodiments. Tothe contrary, reference to embodiments of the present disclosure isintended to cover alternatives, modifications, and equivalents as may beincluded within the spirit and scope of the embodiments of the presentdisclosure as defined by the appended claims.

Embodiments

The embodiments listed below are presented in numbered form forconvenience and in ease and clarity of reference in referring back tomultiple embodiments.

In a first embodiment, the invention provides a compound of Formula I orFormula II:

or a pharmaceutically acceptable salt thereof, a tautomer thereof, apharmaceutically acceptable salt of the tautomer, a stereoisomer of anyof the foregoing, or a mixture thereof,wherein: R¹ is an unsubstituted monocyclic C₃-C₈ cycloalkyl, anunsubstituted C₅-C₈ polycyclic cycloalkyl, an unsubstituted monocyclicC₄-C₈ cycloalkenyl, a monocyclic C₃-C₈ cycloalkyl substituted with 1, 2,3, or 4 R^(1a) substituents, a C₅-C₈ polycyclic cycloalkyl substitutedwith 1, 2, or 3 R^(1a) substituents, or a monocyclic C₄-C₈ cycloalkenylsubstituted with 1, 2, or 3 R^(1a) substituents;

R^(1a) in each instance is independently selected from —F, —Cl, —Br, —I,—CN, —OH, ═O, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆perhaloalkyl), —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl,—C₂-C₄ alkenyl, ═CH₂, ═CH—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-OH, —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)-OH, —(C₁-C₆haloalkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ perhaloalkyl)-OH, —(C₁-C₆perhaloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,—C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂,—C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —NHS(═O)₂—(C₁-C₆ alkyl),—S(═O)₂—(C₁-C₆ alkyl), a phenyl group, or a monocyclic heteroaryl groupwith 5 or 6 ring members containing 1, 2, or 3 heteroatoms independentlyselected from N, O, or S, wherein the R^(1a) phenyl and R^(1a)heteroaryl groups are unsubstituted or are substituted with 1, 2, or 3,R^(1a′) substituents; and further wherein two R^(1a) groups on a singlecarbon atom of a monocyclic C₃-C₈ cycloalkyl R¹ group may join togetherwith the carbon atom to which they are attached to form a heterocyclicring having 3 to 6 members of which 1 or 2 are heteroatoms independentlyselected from O, N, and S;

R^(1a′) is in each instance, independently selected from —F, —Cl, —Br,—I, —CN, —OH, O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆perhaloalkyl), —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl,—C₂-C₄ alkenyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl),—(C₁-C₆ haloalkyl)-OH, —(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆perhaloalkyl)-OH, —(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂,—NHS(═O)₂—(C₁-C₆ alkyl), or —S(═O)₂—(C₁-C₆ alkyl);

R² is selected from —H, or C₁-C₄ alkyl or is absent in the compounds ofFormula II;

R³ is selected from a group of formula —(CR^(3b)R^(3c))-Q, a group offormula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q, a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—C(═O)-Q, a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—CH(OH)-Q, a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—(CR^(3f)R^(3g))-Q, a group of formula—(C₃-C₈ cycloalkyl)-Q, or a group of formula -(heterocyclyl)-Q, whereinthe heterocyclyl of the -(heterocyclyl)-Q group has 5 to 7 ring membersof which 1, 2, or 3 are heteroatoms independently selected from N, O, orS and is unsubstituted or is substituted with 1, 2, or 3 R^(3h)substituents, and further wherein the C₃-C₈ cycloalkyl of the —(C₃-C₈cycloalkyl)-Q group is unsubstituted or is substituted with 1 or 2R^(3h) substituents;

R^(3b) and R^(3c) are independently selected from —H, —F, —Cl, —CN,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or—N(C₁-C₆ alkyl)₂;

R^(3d) and R^(3e) are independently selected from —H, —F, —Cl, —CN,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-O—(C₁-C₆alkyl)-phenyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl),—NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;

R^(3f) and R^(3g) are independently selected from —H, —F, —Cl, —CN,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₂-C₆ alkenyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or—N(C₁-C₆ alkyl)₂;

R^(3h) in each instance is independently selected from —F, —Cl, —CN,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)—(C₃-C₆ cycloalkyl),—C(═O)—O—(C₁-C₆ alkyl), oxo, or —C(═O)-(heterocyclyl), wherein theheterocyclyl group of the R^(h)—C(═O)-(heterocyclyl) has 5 or 6 ringmembers of which 1 or 2 are heteroatoms independently selected from N,or S or has 3 or 4 ring members of which 1 is a heteroatom selected fromN, O, or S;

Q is a monocyclic or bicyclic C₆-C₀ aryl group, a monocyclic or bicyclicheteroaryl group with 5 to 10 ring members containing 1, 2, or 3heteroatoms independently selected from N, O, or S, a C₃-C₈ cycloalkylgroup, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3heteroatoms independently selected from N, O, or S, wherein the C₆-C₁₀aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups areunsubstituted or are substituted with 1, 2, 3, or 4 R^(Q) substituents;and further wherein the Q heterocyclyl group may additionally besubstituted with 1 or 2 oxo substituents, and the Q heteroaryl group mayinclude an N-oxide if the heteroaryl includes a N heteroatom;

R^(Q) in each instance is independently selected from —F, —Cl, —Br, —I,—CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —C₂-C₆alkenyl, —C₂-C₆ alkynyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl),—O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,—NHC(═O)(C₁-C₆ alkyl), —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂,—S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆alkyl), —(C₁-C₆ alkyl)-NH₂, —(C₁-C₆ alkyl)-NH—(C₁-C₆ alkyl), —(C₁-C₆alkyl)-N—(C₁-C₆ alkyl)₂, phenyl, a heterocyclyl group, a —(C₁-C₆alkyl)heterocyclyl group, or a heteroaryl group with 5 or 6 ring membersand 1, 2, or 3, heteroatoms independently selected from N, O, or S,wherein the heterocyclyl groups of the R^(Q) heterocyclyl and —(C₁-C₆alkyl)heterocyclyl groups have 3 to 6 ring members of which 1 or 2 areheteroatoms independently selected from N, O, or S, and further whereinthe heterocyclyl and the heterocyclyl of the —(C₁-C₆ alkyl)heterocyclylR^(Q) groups may be further substituted with one or two oxo substituentsand a substituent selected from —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₆alkyl, or —C(═O)—(C₁-C₆ alkyl);

R⁴ is selected from a monocyclic or bicyclic C₆-C₁₀ aryl group, amonocyclic or bicyclic heteroaryl group with 5 to 10 ring memberscontaining 1, 2, or 3 heteroatoms independently selected from N, O, orS, a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring memberscontaining 1, 2, 3, or 4 heteroatoms independently selected from N, O,or S, a monocyclic 3-6 membered cycloalkyl group, or a straight orbranched chain C₁-C₆ alkyl group, wherein the C₆-C₁ aryl, theheteroaryl, the heterocyclyl, and the cycloalkyl R⁴ group areunsubstituted or are substituted with 1, 2, 3, or 4 R^(4a) substituents,and further wherein the straight or branched chain C₁-C₆ alkyl R⁴ groupis unsubstituted or is substituted with 1, 2, or 3 R^(4b) substituents;

R^(4a) in each instance is independently selected from —F, —Cl, —Br, —I,—CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —OH, —O—(C₁-C₆ alkyl),—O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆ alkyl-OH)₂, —C(═O)—(C₁-C₆alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆alkyl), —C(═O)N(C₁-C₆ alkyl)₂, phenyl, —S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆alkyl)-heterocyclyl, or heterocyclyl wherein the heterocyclyl of the—(C₁-C₆ alkyl)-heterocyclyl and heterocyclyl R^(4a) groups is a 3-6membered ring comprising 1 or 2 heteroatoms independently selected fromN, O, or S, and is unsaturated or partially unsaturated and isoptionally substituted with 1 or 2 oxo substituents, and further whereinthe heterocyclyl of the R⁴ group may be further substituted with 1 oxosubstituent; and

R^(4b) in each instance is selected from —F, —Cl, —Br, —I, —CN, —OH,—O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂,—NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆alkyl-OH)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl),—C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, or,—S(═O)₂—(C₁-C₆ alkyl);

wherein if R¹ is an unsubstituted cyclopropyl, if R⁴ is an unsubstitutedcyclopropyl group, or if R⁴ is a substituted or unsubstituted straightor branched chain C₁-C₆ alkyl group, then at least one of the followingis true:

-   -   (a) if R⁴ is an unsubstituted cyclopropyl group, then R³ is a        group of formula -(heterocyclyl)-Q or R³ is a group of formula        —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q and at least one of R^(3d),        R^(3e), R^(3f), or R^(3g) is not —H;    -   (b) if R¹ is an unsubstituted cyclopropyl, then R⁴ is a        substituted or unsubstituted monocyclic or bicyclic C₆-C₀ aryl        group, a substituted or unsubstituted monocyclic or bicyclic        heteroaryl group with 5 to 10 ring members containing 1, 2, or 3        heteroatoms independently selected from N, O, or S, or is a        substituted or unsubstituted monocyclic or bicyclic heterocyclyl        group with 5 to 10 ring members containing 1, 2, 3, or 4        heteroatoms independently selected from N, O, or S, a monocyclic        3-6 membered cycloalkyl group; or    -   (c) if R⁴ is a substituted or unsubstituted straight or branched        chain C₁-C₆ alkyl group, then R³ is a group of formula        -(heterocyclyl)-Q or R³ is a group of formula        —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q and at least one of R^(3d),        R^(3e), R^(3f), or R^(3g) is not —H.

In some embodiments, if R⁴ is a substituted or unsubstituted straight orbranched chain C₁-C₆ alkyl group or if R⁴ is an unsubstitutedcyclopropyl group, then R³ is a group of formula -(heterocyclyl)-Q or R³is a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q and at leastone of R^(3d), R^(3e), R^(3f), or R^(3g) is not —H and Q is selectedfrom an unsubstituted or substituted monocyclic or bicyclic heteroarylgroup with 5 to 10 ring members containing 1, 2, or 3 heteroatomsindependently selected from N, O, or S, an unsubstituted or substitutedC₃-C₈ cycloalkyl group, or an unsubstituted or substituted 3 to 10membered heterocyclyl group containing 1, 2, or 3 heteroatomsindependently selected from N, O, or S.

In some embodiments, if R⁴ is a substituted or unsubstituted straight orbranched chain C₁-C₆ alkyl group or if R⁴ is an unsubstitutedcyclopropyl group, then R³ is a group of formula -(heterocyclyl)-Q or R³is a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q and at leastone of R^(3d), R^(3e), R^(3f), or R^(3g) is not —H and Q is selectedfrom an unsubstituted or substituted monocyclic or bicyclic heteroarylgroup with 5 to 10 ring members containing 1, 2, or 3 heteroatomsindependently selected from N, O, or S.

In some embodiments, if R⁴ is a substituted or unsubstituted straight orbranched chain C₁-C₆ alkyl group or if R⁴ is an unsubstitutedcyclopropyl group, then R³ is a group of formula -(heterocyclyl)-Q or R³is a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q and at leastone of R^(3d), R^(3e), R^(3f), or R^(3g) is not —H and Q is selectedfrom an unsubstituted or substituted monocyclic heteroaryl group with 6ring members containing 1, 2, or 3 heteroatoms independently selectedfrom N, O, or S.

2. The compound of embodiment 1 or the pharmaceutically acceptable saltthereof, the tautomer thereof, the pharmaceutically acceptable salt ofthe tautomer, the stereoisomer of any of the foregoing, or the mixturethereof, wherein R³ is selected from a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q, or a group of formula-(heterocyclyl)-Q.

3. The compound of embodiment 2 or the pharmaceutically acceptable saltthereof, the tautomer thereof, the pharmaceutically acceptable salt ofthe tautomer, the stereoisomer of any of the foregoing, or the mixturethereof, wherein R³ is a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q.

4. The compound of embodiment 3 or the pharmaceutically acceptable saltthereof, the tautomer thereof, the pharmaceutically acceptable salt ofthe tautomer, the stereoisomer of any of the foregoing, or the mixturethereof, wherein R³ is a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q and further wherein,

R^(3d) and R^(3e) are independently selected from —H, —C₁-C₆ alkyl,—(C₁-C₆ alkyl)-OH, or —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl); and

R^(3f) and R^(3g) are independently selected from —H, —F, —C₁-C₆ alkyl,—C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), or —O—(C₂-C₆ alkenyl).

5. The compound of embodiment 3 or the pharmaceutically acceptable saltthereof, the tautomer thereof, the pharmaceutically acceptable salt ofthe tautomer, the stereoisomer of any of the foregoing, or the mixturethereof, wherein R³ is a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q and further wherein,

R^(3d) and R^(3e) are independently selected from —H, or —C₁-C₆ alkyl;and

R^(3f) and R^(3g) are independently selected from —H, —C₁-C₆ alkyl, —OH,or —O—(C₁-C₆ alkyl).

6. The compound of any one of embodiments 3-5 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein at least one of R^(3d),R^(3e), R^(3f), or R^(3g) is not —H.

7. The compound of any one of embodiments 3-5 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein at least one of R^(3d),R^(3e), R^(3f), or R^(3g) is a —C₁-C₆ alkyl.

8. The compound of embodiment 2 or the pharmaceutically acceptable saltthereof, the tautomer thereof, the pharmaceutically acceptable salt ofthe tautomer, the stereoisomer of any of the foregoing, or the mixturethereof, wherein R³ is a group of formula -(heterocyclyl)-Q.

9. The compound of embodiment 8 or the pharmaceutically acceptable saltthereof, the tautomer thereof, the pharmaceutically acceptable salt ofthe tautomer, the stereoisomer of any of the foregoing, or the mixturethereof, wherein the heterocyclyl of the -(heterocyclyl)-Q R³ group is apiperidinyl that is unsubstituted or is substituted with 1 or 2 R^(3h)substituent.

10. The compound of embodiment 8 or 9 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein the heterocyclyl of the -(heterocyclyl)-Q R³group is a piperidinyl that is unsubstituted or is substituted with 1 or2 R^(3h) substituent independently selected from —OH, or —O—(C₁-C₆alkyl).

11. The compound of any one of embodiments 1, 2, or 8-10 or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof, wherein R³ is selectedfrom

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule.

12. The compound of any one of embodiments 1, 2, or 8-10 or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof, wherein R³ is selectedfrom

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule.

13. The compound of any one of embodiments 1, 2, or 8-10 or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof, wherein R³ is selectedfrom

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule.

14. The compound of embodiment 1 or embodiment 2 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R³ is selected from

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule.

15. The compound of embodiment 1 or embodiment 2 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R³ is selected from

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule.

16. The compound of embodiment 1 or embodiment 2 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R³ is

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule.

17. The compound of embodiment 1 or embodiment 2 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R³ is

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule.

18. The compound of embodiment 1 or embodiment 2 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R³ is

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule.

19. The compound of embodiment 1 or embodiment 2 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R³ is selected from

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule.

20. The compound of embodiment 1 or embodiment 2 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R³ is

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule.

21. The compound of any one of embodiments 1-20 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein Q is selected frompyrimidinyl, pyrazinyl, pyridinyl, or phenyl, any of which may beunsubstituted or substituted with 1, 2, or 3 R^(Q) substituents.

22. The compound of any one of embodiments 1-20 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein Q is an unsubstituted phenylor is a phenyl substituted with 1, 2, or 3 R^(Q) substituents.

23. The compound of any one of embodiments 1-20 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein Q is a monocyclic heteroarylgroup with 5 or 6 ring members containing 1 or 2 heteroatoms selectedfrom N, O, or S and Q is unsubstituted or is substituted with 1 or 2R^(Q) substituents.

24. The compound of any one of embodiments 1-20 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein Q is a pyrimidinyl,pyridinyl, or pyrazinyl group and Q is unsubstituted or is substitutedwith 1, 2, or 3 R^(Q) substituents.

25. The compound of any one of embodiments 1-20 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein Q is a pyrimidinyl group andQ is unsubstituted or is substituted with 1, 2, or 3 R^(Q) substituents.

26. The compound of any one of embodiments 1-25 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R^(Q) in each instance isindependently selected from —F, —Cl, —Br, —CN, —C₁-C₆ alkyl, —C₁-C₆haloalkyl, —C₁-C₆ perhaloalkyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl),or —O—(C₁-C₆ perhaloalkyl).

27. The compound of any one of embodiments 1-25 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R^(Q) in each instance isindependently selected from —F, —Cl, —Br, —CN, or —CH₃.

28. The compound of any one of embodiments 1-20 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein Q is selected from

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule.

29. The compound of any one of embodiments 1-20 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein Q is selected from

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule.

30. The compound of embodiment 29 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein Q is

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule.

31. The compound of embodiment 29 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein Q is

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule.

32. The compound of embodiment 29 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein Q is

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule.

33. The compound of embodiment 29 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein Q is

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule.

34. The compound of embodiment 29 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein Q is

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule.

35. The compound of any one of embodiments 1-34 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R² is —H or is absent in thecompounds of Formula II.

36. The compound of any one of embodiments 1-35 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R⁴ is a phenyl, pyridinyl, orpyrimidinyl, any of which may be unsubstituted or substituted with 1, 2,or 3 R^(4a) substituents.

37. The compound of any one of embodiments 1-35 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R⁴ is a cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or tetrahydropyranyl, any of whichmay be unsubstituted or substituted with 1, 2, or 3 R^(4a) substituents.

38. The compound of any one of embodiments 1-37 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R^(4a) is in each instanceindependently selected from —F, —Br, —CN, —C₁-C₆ alkyl, —C₁-C₆haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-OH, —OH, —O—(C₁-C₆alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C(═O)OH,—C(═O)—O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,—NH(C₁-C₆ alkyl-OH), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), or —C(═O)N(C₁-C₆alkyl)₂.

39. The compound of embodiment 38 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein R^(4a) is in each instance independentlyselected from —CH₃, —F, —Cl, —Br, —CN, —CF₃, —OCH₃, or —OCHF₂.

40. The compound of embodiment 38 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein R^(4a) is in each instance independentlyselected from —F or, —OCH₃.

41. The compound of any one of embodiments 1-35 or the pharmaceuticallyacceptable salt thereof, the stereoisomer of any of the foregoing, orthe mixture thereof, wherein R⁴ is selected from

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule.

42. The compound of any one of embodiments 1-35 or the pharmaceuticallyacceptable salt thereof, the stereoisomer of any of the foregoing, orthe mixture thereof, wherein R⁴ is selected from

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule.

43. The compound of any one of embodiments 1-35 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R⁴ is a phenyl or pyrimidinylsubstituted with 1 or 2 R^(4a) substituents.

44. The compound of embodiment 43 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein the R^(4a) substituents are —O—(C₁-C₂ alkyl)groups.

45. The compound of embodiment 43 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein R⁴ is

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule.

46. The compound of any one of embodiments 1-45 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R¹ is an unsubstitutedmonocyclic C₃-C₈ cycloakyl or is a monocyclic C₃-C₈ cycloakylsubstituted with 1, 2, 3, or 4 R^(1a) substituents.

47. The compound of any one of embodiments 1-45 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R¹ is an unsubstitutedcyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group or is acyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group substitutedwith 1, 2, 3, or 4 R^(1a) substituents.

48. The compound of any one of embodiments 1-45 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R¹ is an unsubstituted C₅-C₈polycyclic cycloalkyl or is a C₅-C₈ polycyclic cycloalkyl substitutedwith 1, 2, or 3 R^(1a) substituents.

49. The compound of any one of embodiments 46-49 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R^(1a) is absent or R^(1a) isindependently selected from —F, —CN, —CH₃, —CF₃, —CHF₂, —CH₂F, —CH₂CHF₂,═CH₂, ═O, —OH, —OCH₃, —OCHF₂, —OCH₂CH₃, or —CH₂OH.

50. The compound of any one of embodiments 1-45 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R¹ is selected from

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule.

51. The compound of embodiment 1, wherein the compound has the FormulaIA

or is the pharmaceutically acceptable salt thereof, the tautomerthereof, the pharmaceutically acceptable salt of the tautomer, thestereoisomer of any of the foregoing, or the mixture thereof, wherein:

R¹ is as defined in embodiment 1;

X is selected from CH or N;

Z is selected from CH or N;

R^(3d) and R^(3e) are independently selected from —H, —C₁-C₆ alkyl,—(C₁-C₆ alkyl)-OH, or —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl); and

R^(3f) and R^(3g) are independently selected from —H, —F, —C₁-C₆ alkyl,—C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), or —O—(C₂-C₆ alkenyl).

Q is a phenyl group or a monocyclic heteroaryl group with 6 ring memberscontaining 1 or 2 N heteroatoms, wherein the phenyl and the monocyclicheteroaryl Q groups are unsubstituted or are substituted with 1, 2, or 3R^(Q) substituent; and

R^(Q) is independently selected from —F, —Cl, —Br, —CN, —C₁-C₆ alkyl,—C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —(C₁-C₆ alkyl)-NH₂ or—S(═O)₂—(C₁-C₆ alkyl).

52. The compound of embodiment 51 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein:

R^(3d) and R^(3e) are independently selected from —H, —C₁-C₆ alkyl, or—(C₁-C₆ alkyl)-OH; and

R^(3f) and R^(3g) are independently selected from —H, —C₁-C₆ alkyl, —OH,or —O—(C₁-C₆ alkyl).

53. The compound of embodiment 51 or embodiment 52 or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof, wherein at least one ofR^(3d), R^(3e), R^(3f), or R^(3g) is not —H.

54. The compound of any one of embodiments 51-53 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein at least one of R^(3d),R^(3e), R^(3f), or R^(3g) is —CH₃.

55. The compound of any one of embodiments 51-54 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R^(Q) in each instance isindependently selected from —F, —Cl, —Br, —CN, or —CH₃.

56. The compound of embodiment 1, wherein the compound has the FormulaIB

or is the pharmaceutically acceptable salt thereof, the tautomerthereof, the pharmaceutically acceptable salt of the tautomer, thestereoisomer of any of the foregoing, or the mixture thereof, wherein:

R¹ is as defined in embodiment 1;

X is selected from CH or N;

Z is selected from CH or N;

R^(3h) is independently selected from —OH, or —O—(C₁-C₆ alkyl); thesubscript p is selected from 0, 1, 2, or 3;

Q is a phenyl group or a monocyclic heteroaryl group with 6 ring memberscontaining 1 or 2 N heteroatoms, wherein the phenyl and the monocyclicheteroaryl Q groups are unsubstituted or are substituted with 1, 2, or 3R^(Q) substituent; and

R^(Q) is independently selected from —F, —Cl, —Br, —CN, —C₁-C₆ alkyl,—C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —(C₁-C₆ alkyl)-NH₂ or—S(═O)₂—(C₁-C₆ alkyl).

57. The compound of embodiment 56 or the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof, wherein p is 0 or 1 and R^(3h) is selected from —OH,—OCH₃, —OCH₂CH₃, or —OCH(CH₃)₂.

58. The compound of any one of embodiments 51-57 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein:

X is CH;

Z is CH; and

Q is a phenyl, a pyrimidinyl, a pyridinyl, or a pyrazinyl any of whichare unsubstituted or are substituted with 1, 2, or 3 R^(Q) substituent.

59. The compound of any one of embodiments 51-57 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein:

X is N;

Z is N; and

Q is a phenyl, a pyrimidinyl, a pyridinyl, or a pyrazinyl any of whichare unsubstituted or are substituted with 1, 2, or 3 R^(Q) substituent.

60. The compound of any one of embodiments 51-59 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R¹ is an unsubstitutedmonocyclic C₃-C₈ cycloakyl or is a monocyclic C₃-C₈ cycloakylsubstituted with 1, 2, 3, or 4 R^(1a) substituents.

61. The compound of any one of embodiments 51-59 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R¹ is an unsubstitutedcyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group or is acyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group substitutedwith 1, 2, 3, or 4 R^(1a) substituents.

62. The compound of any one of embodiments 51-59 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R¹ is an unsubstituted C₅-C₈polycyclic cycloalkyl or is a C₅-C₈ polycyclic cycloalkyl substitutedwith 1, 2, or 3 R^(1a) substituents.

63. The compound of any one of embodiments 51-59 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R^(1a) is absent or R^(1a) isindependently selected from —F, —CN, —CH₃, —CF₃, —CHF₂, —CH₂F, —CH₂CHF₂,═CH₂, ═O, —OH, —OCH₃, —OCHF₂, —OCH₂CH₃, or —CH₂OH.

64. The compound of any one of embodiments 51-59 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R¹ is selected from

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule.

65. The compound of embodiment 1, wherein the compound is selected from

-   2-(4-chlorophenyl)-N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide;-   2-(4-chlorophenyl)-N-(5-cyclopentyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide;-   (2S,3R)—N-(5-cyclopropyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide;-   (2S,3R)—N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide;-   (2S,3R)—N-(5-cyclohexyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-cyclohexyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   N-(4-(2-bromo-6-methoxyphenyl)-5-cyclopentyl-4H-1,2,4-triazol-3-yl)-1-(4-chlorophenyl)methanesulfonamide;-   1-(4-chlorophenyl)-N-(5-cyclopentyl-4-(2,6-dibromophenyl)-4H-1,2,4-triazol-3-yl)methanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-cyclopentyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-((1R)-2,2-dimethylcyclopropyl)-4-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-((1    S)-2,2-dimethylcyclopropyl)-4-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R)-2,2-dimethylcyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1    S)-2,2-dimethylcyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-cyclopropyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-((1R)-2,2-dimethylcyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-((1    S)-2,2-dimethylcyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-((2r,3S,5    S,6r,7S,8r)-pentacyclo[4.2.0.0˜2,5˜.0·3,8˜.    0˜4,7˜]oct-1-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)—N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide;-   (1    S,2S)—N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-1-(2-propanyloxy)-2-propanesulfonamide;-   (2S,3R)—N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide;-   (2S,3R)-3-(5-chloro-2-pyrimidinyl)-N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide;-   (1    S,2S)—N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrazinyl)-1-(2-propanyloxy)-2-propanesulfonamide;-   (2S,3R)-3-(5-chloro-2-pyridinyl)-N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide;-   (2S,3R)—N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrazinyl)-2-butanesulfonamide;-   (1    S,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-(2-propanyloxy)-2-propanesulfonamide;-   (1R,2S)—N-(5-cyclobutyl-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyridin-2-yl)-N-(5-cyclobutyl-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)—N-(5-cyclobutyl-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methoxypyrimidin-2-yl)propane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-cyclobutyl-4-(2,6-difluorophenyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-cyclobutyl-4-(1,3-dimethoxypropan-2-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-cyclobutyl-4-(1-(methoxymethyl)cyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-cyclobutyl-4-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-((1R)-2,2-difluorocyclopropyl)-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-((1    S)-2,2-difluorocyclopropyl)-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-((1R)-6-oxaspiro[2.5]oct-1-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-((1    S)-6-oxaspiro[2.5]oct-1-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-((1    S)-spiro[2.2]pent-1-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-((1R)-spiro[2.2]pent-1-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1    S,2R)-2-ethoxycyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,2S)-2-ethoxycyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1    S,2S)-2-ethoxycyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,2R)-2-ethoxycyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(3-methylidenecyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3,3-dimethylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(3,3-dimethylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(cis-3-cyanocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(trans-3-cyanocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(cis-3-(hydroxymethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(trans-3-(hydroxymethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (2S,3R)-3-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(1-(2-pyridinyl)cyclopropyl)-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide;-   (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(1-(2-pyridinyl)cyclopropyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide;-   (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(1-(3-pyridinyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-cyclobutyl-4-(2-propanyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(cis-3-(hydroxymethyl)cyclobutyl)-4-(1-(methoxymethyl)cyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(trans-3-(hydroxymethyl)cyclobutyl)-4-(1-(methoxymethyl)cyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(1,3-dimethoxy-2-propanyl)-5-(trans-3-(hydroxymethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;    or-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(1,3-dimethoxy-2-propanyl)-5-(cis-3-(hydroxymethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;    or    the pharmaceutically acceptable salt thereof, the tautomer thereof,    the pharmaceutically acceptable salt of the tautomer, the    stereoisomer of any of the foregoing, or the mixture thereof.

66. The compound of embodiment 1, wherein the compound is selected from(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-(2-fluorocyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;

-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-(2,2-difluorocyclopropyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-(2-(trifluoromethyl)cyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-(2,2-difluoro-3-methylcyclopropyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-(2-(difluoromethyl)cyclopropyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-(1-(2,2-difluoroethyl)cyclopropyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-(1-(trifluoromethyl)cyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-(3,3-difluorocyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-(3-hydroxycyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-(3-(hydroxymethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-(3-oxocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-(3-cyanocyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-(2-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-(1-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-(1-hydroxycyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-(4-(trifluoromethyl)bicyclo[1.1.1]pentan-2-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-(3-(difluoromethoxy)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-(2-(fluoromethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-(2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-(1-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-(1-(trifluoromethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-(2,2-difluorocyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-(1-hydroxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-(cyclopent-3-en-1-yl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-(3,3-difluorocyclopentyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-(2,2-difluorocyclopentyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-(3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-(1-(difluoromethyl)cyclopentyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-(3-fluorocyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)—N-(5-(bicyclo[3.1.0]hexan-3-yl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-(2-(hydroxymethyl)cyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-(4-(hydroxymethyl)cyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-(2-hydroxycyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-(4-oxocyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-(4-(difluoromethoxy)cyclohexyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)piperidine-3-sulfonamide;-   N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-5-methoxy-1-(5-methylpyrimidin-2-yl)piperidine-3-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-cyclobutyl-4-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((S)-2,2-dimethylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;    or-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((R)-2,2-dimethylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;    or    the pharmaceutically acceptable salt thereof, the tautomer thereof,    the pharmaceutically acceptable salt of the tautomer, the    stereoisomer of any of the foregoing, or the mixture thereof.

67. The compound of embodiment 1, wherein the compound is selected from

-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-cyclopentyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (2S,3R)—N-(5-cyclopentyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide;-   (2S,3R)—N-(5-cyclopentyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-cyclohexyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (2S,3R)—N-(5-cyclohexyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (2S,3R)—N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide;-   (1R,2S)—N-(5-cyclopropyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide;-   (2S,3R)—N-(5-cyclopropyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-cyclopropyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;    or-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((2R,3S,4S,5S,6S,7R,8S)-cuban-1-yl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;    or    the pharmaceutically acceptable salt thereof, the tautomer thereof,    the pharmaceutically acceptable salt of the tautomer, the    stereoisomer of any of the foregoing, or the mixture thereof.

68. The compound of embodiment 1, wherein the compound is selected from

-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(trans-3-(hydroxymethyl)cyclobutyl)-4-(1-(methoxymethyl)cyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(cis-3-(hydroxymethyl)cyclobutyl)-4-(1-(methoxymethyl)cyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-cyclopropyl-5-(trans-3-(hydroxymethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-cyclopropyl-5-(cis-3-(hydroxymethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(trans-3-(hydroxymethyl)cyclobutyl)-4-(2-propanyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(cis-3-(hydroxymethyl)cyclobutyl)-4-(2-propanyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)—N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide;-   (2S,3R)—N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrazinyl)-2-butanesulfonamide;-   (1    S,2S)—N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrazinyl)-1-(2-propanyloxy)-2-propanesulfonamide;-   (1R,2S)—N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide;-   (1    S,2S)—N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-1-(2-propanyloxy)-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(cis-4-(difluoromethyl)cyclohexyl)-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(trans-4-(difluoromethyl)cyclohexyl)-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1R,2S)-2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1S,2R)-2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1R,2R)-2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1S,2S)-2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(3,3-difluorocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1r,3S)-3-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1s,3R)-3-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1r,3S)-3-(trifluoromethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1s,3R)-3-(trifluoromethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1r,3S)-3-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1s,3R)-3-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1r,3S)-3-chlorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1s,3R)-3-chlorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1r,3S)-3-methoxycyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1s,3R)-3-methoxycyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((R)-2,2-difluorocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((S)-2,2-difluorocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1s,3R)-3-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1r,3S)-3-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1s,3R)-3-chlorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1r,3S)-3-chlorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(5-((1R,2S)-2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)butane-2-sulfonamide;-   (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(5-((1    S,2R)-2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)butane-2-sulfonamide;-   (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(5-((1R,2R)-2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)butane-2-sulfonamide;-   (2 S,3R)-3-(5-chloropyrimidin-2-yl)-N-(5-((1    S,2S)-2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)butane-2-sulfonamide;-   (1    S,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1R,2S)-2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-isopropoxypropane-2-sulfonamide;-   (1 S,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1    S,2R)-2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-isopropoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1R,2S)-2-cyanocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1    S,2R)-2-cyanocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1R,2R)-2-cyanocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1s,4R)-4-fluorocyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1r,4S)-4-fluorocyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1s,3R)-3-(trifluoromethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1r,3S)-3-(trifluoromethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1    S,2S)-2-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1R,2R)-2-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1R,2S)-2-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1    S,2R)-2-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1    S,2S)-2-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1R,2R)-2-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1    S,2R)-2-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1R,2S)-2-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)—N-(5-((1r,3S)-3-chlorocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide;-   (1R,2S)—N-(5-((1s,3R)-3-chlorocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide;-   (2S,3R)—N-(5-((1r,3S)-3-chlorocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide;-   (2S,3R)—N-(5-((1s,3R)-3-chlorocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide;-   (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(spiro[2.3]hexan-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide;-   (1R,2S)—N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-(spiro[2.3]hexan-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide;-   (2S,3R)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(spiro[2.3]hexan-5-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,2R)-2-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1    S,2R)-2-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1    S,2S)-2-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,2S)-2-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)—N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-(2,2-difluoroethoxy)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1s,4R)-4-methoxycyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1r,4S)-4-methoxycyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1s,4R)-4-(trifluoromethyl)cyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1r,4S)-4-(trifluoromethyl)cyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(spiro[2.3]hexan-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(spiro[3.3]heptan-2-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(trans-3-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(cis-3-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1s,3R)-3-fluoro-3-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1r,3S)-3-fluoro-3-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((R)-2,2-dimethyl-3-oxocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((S)-2,2-dimethyl-3-oxocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1r,4R)-4-cyanocyclohexyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1s,4R)-4-cyanocyclohexyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-(3,3-dichlorocyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((3R,5    s)-1,1-difluorospiro[2.3]hexan-5-yl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((3    S,5r)-1,1-difluorospiro[2.3]hexan-5-yl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   2-(5-chloro-2-pyrimidinyl)-N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide;-   (1    S,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-cyclobutyl-4-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)-1-(2-propanyloxy)-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1    S,3    S)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,3R)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,3    S)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1    S,3R)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)—N-(5-(bicyclo[1.1.1]pentan-1-yl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((R)-3-oxocyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((S)-3-oxocyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((S)-spiro[2.2]pentan-1-yl)-4H-1,2,4-triazol-3-yl)butane-2-sulfonamide;-   (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((R)-spiro[2.2]pentan-1-yl)-4H-1,2,4-triazol-3-yl)butane-2-sulfonamide;-   (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(5-((R)-2,2-difluorocyclopropyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)butane-2-sulfonamide;-   (2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(5-((S)-2,2-difluorocyclopropyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)butane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((S)-spiro[2.2]pentan-1-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((R)-spiro[2.2]pentan-1-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1    S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(trans-3-methoxycyclobutyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-1-(2-propanyloxy)-2-propanesulfonamide;-   (1    S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(cis-3-methoxycyclobutyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-1-(2-propanyloxy)-2-propanesulfonamide;-   (1    S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(cis-4-hydroxybicyclo[1.1.1]pentan-2-yl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide;-   (1    S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(trans-4-hydroxybicyclo[1.1.1]pentan-2-yl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide;-   (1    S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-((R)-3-oxocyclopentyl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide;-   (1    S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-((S)-3-oxocyclopentyl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide;-   (1    S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(trans-3-hydroxy-3-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-1-(2-propanyloxy)-2-propane    sulfonamide;-   (1    S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(cis-3-hydroxy-3-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-1-(2-propanyloxy)-2-propanesulfonamide;-   (1    S,2S)—N-(5-((1R)-3,3-difluorocyclopentyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-1-(2-propanyloxy)-2-propanesulfonamide;-   (1 S,2S)—N-(5-((1    S)-3,3-difluorocyclopentyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-1-(2-propanyloxy)-2-propanesulfonamide;-   (1    S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-((1R,2S)-2-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide;-   (1 S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-((1    S,2R)-2-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide;-   (1    S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-((1R,2R)-2-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide;-   (1 S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-((1    S,2S)-2-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(spiro[3.3]heptan-2-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(3,3-dimethoxycyclobutyl)-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1s,3S)-3-fluoro-3-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1r,3S)-3-fluoro-3-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(spiro[2.3]hexan-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(2-oxaspiro[3.3]heptan-6-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;    or-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-cyclopentyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide;    or    the pharmaceutically acceptable salt thereof, the tautomer thereof,    the pharmaceutically acceptable salt of the tautomer, the    stereoisomer of any of the foregoing, or the mixture thereof.

69. A pharmaceutical composition, comprising the compound of any one ofembodiments 1-68 or the pharmaceutically acceptable salt thereof, thetautomer thereof, the pharmaceutically acceptable salt of the tautomer,the stereoisomer of any of the foregoing, or the mixture thereof, and atleast one pharmaceutically acceptable excipient.

70. A pharmaceutical composition, comprising the compound of any one ofembodiments 1-68 or the pharmaceutically acceptable salt thereof and atleast one pharmaceutically acceptable excipient.

71. A pharmaceutical composition, comprising the compound of any one ofembodiments 1-68 and at least one pharmaceutically acceptable excipient.

72. A pharmaceutical composition, comprising the pharmaceuticallyacceptable salt of the compound of any one of embodiments 1-68 and atleast one pharmaceutically acceptable excipient.

73. The pharmaceutical composition of any one of embodiments 69-72,further comprising a therapeutic agent selected from an α-blocker, aβ-blocker, an angiotensin converting enzyme (ACE) inhibitor, anangiotensin-receptor blocker (ARB), a calcium channel blocker, adiuretic, an inhibitor of the funny current, a myosin activator, or aneutral endopeptidase (NEP) inhibitor.

74. The pharmaceutical composition of any one of embodiments 69-72,further comprising a therapeutic agent selected from an angiotensinconverting enzyme (ACE) inhibitor or an angiotensin-receptor blocker(ARB).

75. A method of treating a cardiovascular condition, the methodcomprising: administering to a subject an effective amount of thecompound of any one of embodiments 1-68 or the pharmaceuticallyacceptable salt thereof, the stereoisomer of any of the foregoing, orthe mixture thereof, or the pharmaceutical composition of any one ofembodiments 69-74.

76. The method of embodiment 75, wherein the cardiovascular condition isheart failure.

77. The method of embodiment 75, wherein the cardiovascular condition isheart failure with reduced ejection fraction.

78. The method of embodiment 75, wherein the cardiovascular condition isheart failure with preserved ejection fraction.

79. The method of embodiment 75, wherein the cardiovascular condition ischronic systolic heart failure or chronic diastolic heart failure.

80. The method of embodiment 75, wherein the cardiovascular condition isacute heart failure.

81. The method of embodiment 75, wherein the cardiovascular condition ishypertension.

82. A method of improving cardiac contractility in a subject sufferingfrom a cardiovascular condition, the method comprising: administering tothe subject an effective amount of the compound of any one ofembodiments 1-68 or the pharmaceutically acceptable salt thereof, thestereoisomer of any of the foregoing, or the mixture thereof, or thepharmaceutical composition of any one of embodiments 69-74, whereincardiac contractility is improved in the subject after administration.

83. A method of increasing ejection fraction in a subject suffering froma cardiovascular condition, the method comprising: administering to thesubject an effective amount of the compound of any one of embodiments1-68 or the pharmaceutically acceptable salt thereof, the stereoisomerof any of the foregoing, or the mixture thereof, or the pharmaceuticalcomposition of any one of embodiments 69-74, wherein the ejectionfraction is increased in the subject after administration.

84. A method of treating a condition in a subject where it is desired toactivate the APJ Receptor, the method comprising: administering to thesubject an effective amount of the compound of any one of embodiments1-68 or the pharmaceutically acceptable salt thereof, the stereoisomerof any of the foregoing, or the mixture thereof or the pharmaceuticalcomposition of any one of embodiments 69-74.

85. The method of embodiment 84, wherein the condition is obesity ordiabetes.

86. The method of embodiment 84, wherein the condition is diabeticnephropathy or chronic kidney disease.

87. The method of any one of embodiments 75-86, wherein the methodincludes administering at least one additional therapeutic agent to thesubject, wherein the additional therapeutic agent is selected from anα-blocker, a β-blocker, an angiotensin converting enzyme (ACE)inhibitor, an angiotensin-receptor blocker (ARB), a calcium channelblocker, a diuretic, an inhibitor of the funny current, a myosinactivator, or a neutral endopeptidase (NEP) inhibitor.

88. The method of any one of embodiments 75-86, wherein the methodincludes administering at least one additional therapeutic agent to thesubject, wherein the additional therapeutic agent is selected from anangiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptorblocker (ARB).

89. A compound of any one of embodiments 1-68 or the pharmaceuticallyacceptable salt thereof, the stereoisomer of any of the foregoing, orthe mixture thereof, or the pharmaceutical composition of any one ofembodiments 69-74 for use in treating a cardiovascular condition.

90. The compound of embodiments 89, wherein the cardiovascular conditionis heart failure.

91. The compound of embodiment 89, wherein the cardiovascular conditionis heart failure with reduced ejection fraction.

92. The compound of embodiment 89, wherein the cardiovascular conditionis heart failure with preserved ejection fraction.

93. The compound of embodiment 89, wherein the cardiovascular conditionis chronic systolic heart failure or chronic diastolic heart failure.

94. The compound of embodiment 89, wherein the cardiovascular conditionis acute heart failure.

95. The compound of embodiment 89, wherein the cardiovascular conditionis hypertension.

96. A compound of any one of embodiments 1-68 or the pharmaceuticallyacceptable salt thereof, the stereoisomer of any of the foregoing, orthe mixture thereof, or the pharmaceutical composition of any one ofembodiments 69-74 for use in activating the APJ Receptor or for treatinga condition where it is desirable to activate the APJ Receptor.

97. The compound of embodiment 96, wherein the condition is obesity ordiabetes.

98. The compound of embodiment 96, wherein the condition is diabeticnephropathy or chronic kidney disease.

99. A use of the compound of any one of embodiments 1-68 or thepharmaceutically acceptable salt thereof, the stereoisomer of any of theforegoing, or the mixture thereof in the preparation of a medicament fortreating a cardiovascular condition.

100. The use of embodiment 99, further comprising a therapeutic agentselected from an α-blocker, a β-blocker, an angiotensin convertingenzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calciumchannel blocker, a diuretic, an inhibitor of the funny current, a myosinactivator, or a neutral endopeptidase (NEP) inhibitor.

101. The use of embodiment 99, further comprising a therapeutic agentselected from an angiotensin converting enzyme (ACE) inhibitor or anangiotensin-receptor blocker (ARB).

102. The use of the compound of any one of embodiments 99-101, whereinthe cardiovascular condition is heart failure.

103. The use of the compound of any one of embodiments 99-101, whereinthe cardiovascular condition is heart failure with reduced ejectionfraction.

104. The use of the compound of any one of embodiments 99-101, whereinthe cardiovascular condition is heart failure with preserved ejectionfraction.

105. The use of the compound of any one of embodiments 99-101, whereinthe cardiovascular condition is chronic systolic heart failure orchronic diastolic heart failure.

106. The use of the compound of any one of embodiments 99-101, whereinthe cardiovascular condition is acute heart failure.

107. The use of the compound of any one of embodiments 99-101, whereinthe cardiovascular condition is hypertension.

108. A use of the compound of any one of embodiments 1-68 or thepharmaceutically acceptable salt thereof, the stereoisomer of any of theforegoing, or the mixture thereof in the preparation of a medicament foractivating the APJ Receptor or treating a condition where it isdesirable to activate the APJ Receptor.

109. The use of embodiment 108, wherein the condition is obesity ordiabetes.

110. The use of embodiment 108, wherein the condition is diabeticnephropathy or chronic kidney disease.

111. A treatment regimen for a cardiovascular disease, the regimencomprising: the compound of any one of embodiments 1-68 or thepharmaceutically acceptable salt thereof, the stereoisomer of any of theforegoing, or the mixture thereof.

112. The treatment regimen of embodiment 111, wherein the regimenfurther comprises a therapeutic agent selected from an α-blocker, aβ-blocker, an angiotensin converting enzyme (ACE) inhibitor, anangiotensin-receptor blocker (ARB), a calcium channel blocker, adiuretic, an inhibitor of the funny current, a myosin activator, or aneutral endopeptidase (NEP) inhibitor.

113. The treatment regimen of embodiment 111, wherein the regimenfurther comprises a therapeutic agent selected from an angiotensinconverting enzyme (ACE) inhibitor or an angiotensin-receptor blocker(ARB).

114. A kit, the kit comprising: the compound of any one of embodiments1-68 or the pharmaceutically acceptable salt thereof, the stereoisomerof any of the foregoing, or the mixture thereof.

115. The kit of embodiment 114, wherein the kit further comprises atherapeutic agent selected from an α-blocker, a β-blocker, anangiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptorblocker (ARB), a calcium channel blocker, a diuretic, an inhibitor ofthe funny current, a myosin activator, or a neutral endopeptidase (NEP)inhibitor.

116. The kit of embodiment 114, wherein the kit further comprises atherapeutic agent selected from an angiotensin converting enzyme (ACE)inhibitor or an angiotensin-receptor blocker (ARB).

117. In another aspect, the invention provides a compound of Formula V,a salt thereof, a tautomer thereof, or a salt of the tautomer:

wherein:

R¹ is an unsubstituted monocyclic C₃-C₈ cycloalkyl, an unsubstitutedC₅-C₈ polycyclic cycloalkyl, an unsubstituted monocyclic C₄-C₈cycloalkenyl, a monocyclic C₃-C₈ cycloalkyl substituted with 1, 2, 3, or4 R^(1a) substituents, a C₅-C₈ polycyclic cycloalkyl substituted with 1,2, or 3 R^(1a) substituents, or a monocyclic C₄-C₈ cycloalkenylsubstituted with 1, 2, or 3 R^(1a) substituents;

R^(1a) in each instance is independently selected from —F, —Cl, —Br, —I,—CN, —OH, ═O, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆perhaloalkyl), —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl,—C₂-C₄ alkenyl, ═CH₂, ═CH—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-OH, —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)-OH, —(C₁-C₆haloalkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ perhaloalkyl)-OH, —(C₁-C₆perhaloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,—C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂,—C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —NHS(═O)₂—(C₁-C₆ alkyl),—S(═O)₂—(C₁-C₆ alkyl), a phenyl group, or a monocyclic heteroaryl groupwith 5 or 6 ring members containing 1, 2, or 3 heteroatoms independentlyselected from N, O, or S, wherein the R^(1a) phenyl and R^(1a)heteroaryl groups are unsubstituted or are substituted with 1, 2, or 3,R^(1a′) substituents; and further wherein two R^(1a) groups on a singlecarbon atom of a monocyclic C₃-C₈ cycloalkyl R¹ group may join togetherwith the carbon atom to which they are attached to form a heterocyclicring having 3 to 6 members of which 1 or 2 are heteroatoms independentlyselected from O, N, and S;

R^(1a′) is in each instance, independently selected from —F, —Cl, —Br,—I, —CN, —OH, O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆perhaloalkyl), —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl,—C₂-C₄ alkenyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl),—(C₁-C₆ haloalkyl)-OH, —(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆perhaloalkyl)-OH, —(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂,—NHS(═O)₂—(C₁-C₆ alkyl), or —S(═O)₂—(C₁-C₆ alkyl);

R³ is selected from a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q, a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—C(═O)-Q, a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—CH(OH)-Q, a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—(CR^(3f)R^(3g))-Q, a group of formula—(C₃-C₈ cycloalkyl)-Q, or a group of formula -(heterocyclyl)-Q, whereinthe heterocyclyl of the -(heterocyclyl)-Q group has 5 to 7 ring membersof which 1, 2, or 3 are heteroatoms independently selected from N, O, orS and is unsubstituted or is substituted with 1, 2, or 3 R^(3h)substituents, and further wherein the C₃-C₈ cycloalkyl of the —(C₃-C₈cycloalkyl)-Q group is unsubstituted or is substituted with 1 or 2R^(3h) substituents;

R^(3d) and R^(3e) are independently selected from —H, —F, —Cl, —CN,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-O—(C₁-C₆alkyl)-phenyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl),—NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;

R^(3f) and R^(3g) are independently selected from —H, —F, —Cl, —CN,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₂-C₆ alkenyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or—N(C₁-C₆ alkyl)₂;

R^(3h) in each instance is independently selected from —F, —Cl, —CN,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)—(C₃-C₆ cycloalkyl),—C(═O)—O—(C₁-C₆ alkyl), oxo, or —C(═O)-(heterocyclyl), wherein theheterocyclyl group of the R^(h)—C(═O)-(heterocyclyl) has 5 or 6 ringmembers of which 1 or 2 are heteroatoms independently selected from N,or S or has 3 or 4 ring members of which 1 is a heteroatom selected fromN, O, or S;

Q is a monocyclic or bicyclic C₆-C₀ aryl group, a monocyclic or bicyclicheteroaryl group with 5 to 10 ring members containing 1, 2, or 3heteroatoms independently selected from N, O, or S, a C₃-C₈ cycloalkylgroup, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3heteroatoms independently selected from N, O, or S, wherein the C₆-C₁₀aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups areunsubstituted or are substituted with 1, 2, 3, or 4 R^(Q) substituents;and further wherein the Q heterocyclyl group may additionally besubstituted with 1 or 2 oxo substituents, and the Q heteroaryl group mayinclude an N-oxide if the heteroaryl includes a N heteroatom;

R^(Q) in each instance is independently selected from —F, —Cl, —Br, —I,—CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —C₂-C₆alkenyl, —C₂-C₆ alkynyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl),—O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,—NHC(═O)(C₁-C₆ alkyl), —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂,—S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆alkyl), —(C₁-C₆ alkyl)-NH₂, —(C₁-C₆ alkyl)-NH—(C₁-C₆ alkyl), —(C₁-C₆alkyl)-N—(C₁-C₆ alkyl)₂, phenyl, a heterocyclyl group, a —(C₁-C₆alkyl)heterocyclyl group, or a heteroaryl group with 5 or 6 ring membersand 1, 2, or 3, heteroatoms independently selected from N, O, or S,wherein the heterocyclyl groups of the R^(Q) heterocyclyl and —(C₁-C₆alkyl)heterocyclyl groups have 3 to 6 ring members of which 1 or 2 areheteroatoms independently selected from N, O, or S, and further whereinthe heterocyclyl and the heterocyclyl of the —(C₁-C₆ alkyl)heterocyclylR^(Q) groups may be further substituted with one or two oxo substituentsand a substituent selected from —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₆alkyl, or —C(═O)—(C₁-C₆ alkyl);

R⁴ is selected from a monocyclic or bicyclic C₆-C₀ aryl group, amonocyclic or bicyclic heteroaryl group with 5 to 10 ring memberscontaining 1, 2, or 3 heteroatoms independently selected from N, O, orS, a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring memberscontaining 1, 2, 3, or 4 heteroatoms independently selected from N, O,or S, a monocyclic 3-6 membered cycloalkyl group, or a straight orbranched chain C₁-C₆ alkyl group, wherein the C₆-C₁ aryl, theheteroaryl, the heterocyclyl, and the cycloalkyl R⁴ group areunsubstituted or are substituted with 1, 2, 3, or 4 R^(4a) substituents,and further wherein the straight or branched chain C₁-C₆ alkyl R⁴ groupis unsubstituted or is substituted with 1, 2, or 3 R^(4b) substituents;

R^(4a) in each instance is independently selected from —F, —Cl, —Br, —I,—CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —OH, —O—(C₁-C₆ alkyl),—O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆ alkyl-OH)₂, —C(═O)—(C₁-C₆alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆alkyl), —C(═O)N(C₁-C₆ alkyl)₂, phenyl, —S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆alkyl)-heterocyclyl, or heterocyclyl wherein the heterocyclyl of the—(C₁-C₆ alkyl)-heterocyclyl and heterocyclyl R^(4a) groups is a 3-6membered ring comprising 1 or 2 heteroatoms independently selected fromN, O, or S, and is unsaturated or partially unsaturated and isoptionally substituted with 1 or 2 oxo substituents, and further whereinthe heterocyclyl of the R⁴ group may be further substituted with 1 oxosubstituent; and

R^(4b) in each instance is selected from —F, —Cl, —Br, —I, —CN, —OH,—O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂,—NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆alkyl-OH)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl),—C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, or,—S(═O)₂—(C₁-C₆ alkyl).

118. The compound of embodiment 117, the salt thereof, the tautomerthereof, or the salt of the tautomer, wherein the compound has any ofthe R¹, R^(1a), R³, R^(3d), , R^(3e), R^(3f), R^(3g), R^(3h), R⁴,R^(4a), Q, or R^(Q), values or combinations of values of any one ofembodiments 2-64.

119. In yet another aspect, the invention provides a method forpreparing a compound of Formula VI, a salt thereof, a tautomer thereof,or a salt of the tautomer:

the method comprising:

-   -   a) cyclizing a compound of Formula V, a salt thereof, a tautomer        thereof, or a salt of the tautomer in the presence of an acid or        a base to form the compound of Formula VI, the salt thereof, the        tautomer thereof, or the salt of the tautomer,

wherein:

R¹ is an unsubstituted monocyclic C₃-C₈ cycloalkyl, an unsubstitutedC₅-C₈ polycyclic cycloalkyl, an unsubstituted monocyclic C₄-C₈cycloalkenyl, a monocyclic C₃—C₈ cycloalkyl substituted with 1, 2, 3, or4 R^(1a) substituents, a C₅-C₈ polycyclic cycloalkyl substituted with 1,2, or 3 R^(1a) substituents, or a monocyclic C₄-C₈ cycloalkenylsubstituted with 1, 2, or 3 R^(1a) substituents;

R^(1a) in each instance is independently selected from —F, —Cl, —Br, —I,—CN, —OH, ═O, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆perhaloalkyl), —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl,—C₂-C₄ alkenyl, ═CH₂, ═CH—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-OH, —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)-OH, —(C₁-C₆haloalkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ perhaloalkyl)-OH, —(C₁-C₆perhaloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,—C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂,—C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —NHS(═O)₂—(C₁-C₆ alkyl),—S(═O)₂—(C₁-C₆ alkyl), a phenyl group, or a monocyclic heteroaryl groupwith 5 or 6 ring members containing 1, 2, or 3 heteroatoms independentlyselected from N, O, or S, wherein the R^(1a) phenyl and R^(1a)heteroaryl groups are unsubstituted or are substituted with 1, 2, or 3,R^(1a′) substituents; and further wherein two R^(1a) groups on a singlecarbon atom of a monocyclic C₃-C₈ cycloalkyl R¹ group may join togetherwith the carbon atom to which they are attached to form a heterocyclicring having 3 to 6 members of which 1 or 2 are heteroatoms independentlyselected from O, N, and S;

R^(1a′) is in each instance, independently selected from —F, —Cl, —Br,—I, —CN, —OH, O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆perhaloalkyl), —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl,—C₂-C₄ alkenyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl),—(C₁-C₆ haloalkyl)-OH, —(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆perhaloalkyl)-OH, —(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂,—NHS(═O)₂—(C₁-C₆ alkyl), or —S(═O)₂—(C₁-C₆ alkyl);

R³ is selected from a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q, a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—C(═O)-Q a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—CH(OH)-Q, a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—(CR^(3f)R^(3g))-Q a group of formula—(C₃-C₈ cycloalkyl)-Q, or a group of formula -(heterocyclyl)-Q, whereinthe heterocyclyl of the -(heterocyclyl)-Q group has 5 to 7 ring membersof which 1, 2, or 3 are heteroatoms independently selected from N, O, orS and is unsubstituted or is substituted with 1, 2, or 3 R^(3h)substituents, and further wherein the C₃-C₈₈ cycloalkyl of the —(C₃-C₈cycloalkyl)-Q group is unsubstituted or is substituted with 1 or 2R^(3h) substituents;

R^(3d) and R^(3e) are independently selected from —H, —F, —Cl, —CN,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-O—(C₁-C₆alkyl)-phenyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl),—NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;

R^(3f) and R^(3g) are independently selected from —H, —F, —Cl, —CN,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₂-C₆ alkenyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or—N(C₁-C₆ alkyl)₂;

R^(3h) in each instance is independently selected from —F, —Cl, —CN,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)—(C₃-C₆ cycloalkyl),—C(═O)—O—(C₁-C₆ alkyl), oxo, or —C(═O)-(heterocyclyl), wherein theheterocyclyl group of the R^(h)—C(═O)-(heterocyclyl) has 5 or 6 ringmembers of which 1 or 2 are heteroatoms independently selected from N,or S or has 3 or 4 ring members of which 1 is a heteroatom selected fromN, O, or S;

Q is a monocyclic or bicyclic C₆-C₀ aryl group, a monocyclic or bicyclicheteroaryl group with 5 to 10 ring members containing 1, 2, or 3heteroatoms independently selected from N, O, or S, a C₃-C₈₈ cycloalkylgroup, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3heteroatoms independently selected from N, O, or S, wherein the C₆-C₁₀aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups areunsubstituted or are substituted with 1, 2, 3, or 4 R^(Q) substituents;and further wherein the Q heterocyclyl group may additionally besubstituted with 1 or 2 oxo substituents, and the Q heteroaryl group mayinclude an N-oxide if the heteroaryl includes a N heteroatom;

R^(Q) in each instance is independently selected from —F, —Cl, —Br, —I,—CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —C₂-C₆alkenyl, —C₂-C₆ alkynyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl),—O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁—C₆ alkyl)₂,—NHC(═O)(C₁-C₆ alkyl), —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂,—S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆alkyl), —(C₁-C₆ alkyl)-NH₂, —(C₁-C₆ alkyl)-NH—(C₁-C₆ alkyl), —(C₁-C₆alkyl)-N—(C₁-C₆ alkyl)₂, phenyl, a heterocyclyl group, a —(C₁-C₆alkyl)heterocyclyl group, or a heteroaryl group with 5 or 6 ring membersand 1, 2, or 3, heteroatoms independently selected from N, O, or S,wherein the heterocyclyl groups of the R^(Q) heterocyclyl and —(C₁-C₆alkyl)heterocyclyl groups have 3 to 6 ring members of which 1 or 2 areheteroatoms independently selected from N, O, or S, and further whereinthe heterocyclyl and the heterocyclyl of the —(C₁-C₆ alkyl)heterocyclylR^(Q) groups may be further substituted with one or two oxo substituentsand a substituent selected from —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₆alkyl, or —C(═O)—(C₁-C₆ alkyl);

R⁴ is selected from a monocyclic or bicyclic C₆-C₀ aryl group, amonocyclic or bicyclic heteroaryl group with 5 to 10 ring memberscontaining 1, 2, or 3 heteroatoms independently selected from N, O, orS, a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring memberscontaining 1, 2, 3, or 4 heteroatoms independently selected from N, O,or S, a monocyclic 3-6 membered cycloalkyl group, or a straight orbranched chain C₁-C₆ alkyl group, wherein the C₆-C₁ aryl, theheteroaryl, the heterocyclyl, and the cycloalkyl R⁴ group areunsubstituted or are substituted with 1, 2, 3, or 4 R^(4a) substituents,and further wherein the straight or branched chain C₁-C₆ alkyl R⁴ groupis unsubstituted or is substituted with 1, 2, or 3 R^(4b) substituents;

R^(4a) in each instance is independently selected from —F, —Cl, —Br, —I,—CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —OH, —O—(C₁-C₆ alkyl),—O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆ alkyl-OH)₂, —C(═O)—(C₁-C₆alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆alkyl), —C(═O)N(C₁-C₆ alkyl)₂, phenyl, —S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆alkyl)-heterocyclyl, or heterocyclyl wherein the heterocyclyl of the—(C₁-C₆ alkyl)-heterocyclyl and heterocyclyl R^(4a) groups is a 3-6membered ring comprising 1 or 2 heteroatoms independently selected fromN, O, or S, and is unsaturated or partially unsaturated and isoptionally substituted with 1 or 2 oxo substituents, and further whereinthe heterocyclyl of the R⁴ group may be further substituted with 1 oxosubstituent; and

R^(4b) in each instance is selected from —F, —Cl, —Br, —I, —CN, —OH,—O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂,—NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆alkyl-OH)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl),—C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, or,—S(═O)₂—(C₁-C₆ alkyl).

120. The method of embodiment 119, wherein R¹, R^(1a), R³, R^(3d),R^(3e), R^(3f), R^(3g), R^(3h), R⁴, R^(4a), Q, or R^(Q), have any of thevalues or combination of values of any one of embodiments 2-64.

121. The method of embodiment 119 or embodiment 120, wherein cyclizingfurther comprises heating the compound of Formula V, the salt thereof,the tautomer thereof, or the salt of the tautomer in the presence of theacid or the base.

122. The method of embodiment 121, wherein heating the compound ofFormula V, the salt thereof, the tautomer thereof, or the salt of thetautomer comprises heating the compound to a temperature of from 50° C.to 100° C.

123. The method of embodiment 121, wherein heating the compound ofFormula V, the salt thereof, the tautomer thereof, or the salt of thetautomer comprises heating the compound to a temperature of from 60° C.to 85° C.

124. The method of any one of embodiments 119-123, wherein the cyclizingof the compound of Formula V, the salt thereof, the tautomer thereof, orthe salt of the tautomer is performed in the presence of the base.

125. The method of any one of embodiments 119-124, wherein the base is ametal hydroxide.

126. The method of embodiment 125, wherein the metal hydroxide isselected from NaOH or LiOH.

127. The method of any one of embodiments 124-126, wherein the cyclizingis carried out in an alcohol solvent.

128. The method of embodiment 127, wherein the alcohol is isopropanol.

129. The method of any one of embodiments 119-123, wherein cyclizingfurther comprises heating the compound of Formula V, the salt thereof,the tautomer thereof, or the salt of the tautomer in the presence of theacid.

130. The method of embodiment 129, wherein the acid is selected from asulfonic acid, a carboxylic acid, polyphosphoric acid, phosphoric acid,sulfuric acid, or hydrochloric acid.

131. The method of embodiment 130, wherein the sulfonic acid ismethanesulfonic acid.

132. The method of embodiment 130, wherein the acid is trifluoroaceticacid, acetic acid, or trichloroacetic acid.

133. The method of any one of embodiments 129-132, wherein the cyclizingis carried out in a cyclic ether, an acyclic ether,N,N-dimethylformamide, or acetonitrile.

134. The method of embodiment 133, wherein the cyclizing is carried outin a cyclic ether.

135. The method of embodiment 134, wherein the cyclic ether is selectedfrom tetrahydrofuran, tetrahydropyran, or 1,4-dioxane.

136. The method of embodiment 134, wherein the cyclic ether is1,4-dioxane.

In some embodiments, the compound is a salt. Such salts may be anhydrousor associated with water as a hydrate. In some embodiments, the compoundmay be in a neutral form as a base or an acid.

Also provided are pharmaceutical compositions that include the compoundor the pharmaceutically acceptable salt thereof, the tautomer thereof,the pharmaceutically acceptable salt of the tautomer, the stereoisomerof any of the foregoing, or the mixture thereof according to any one ofthe embodiments and at least one pharmaceutically acceptable excipient,carrier or diluent. In some such embodiments, the compound or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof according to any one of theembodiments is present in an amount effective for the treatment of acardiovascular condition or other condition such as obesity or diabetes,for activating the APJ Receptor. In some embodiments, the pharmaceuticalcomposition is formulated for oral delivery whereas in otherembodiments, the pharmaceutical composition is formulated forintravenous delivery. In some embodiments, the pharmaceuticalcomposition is formulated for oral administration once a day or QD, andin some such formulations is a tablet.

In some embodiments, the subject is a mammal. In some such embodiments,the mammal is a rodent. In other such embodiments, the mammal is acanine. In still other embodiments, the subject is a primate and, insome such embodiments, is a human.

The pharmaceutical compositions or formulations for the administrationof the compounds of this invention may conveniently be presented in unitdosage form and may be prepared by any of the methods well known in theart. All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition, the active object compound is includedin an amount sufficient to produce the desired effect upon the processor condition of diseases.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions. Suchcompositions may contain one or more agents selected from sweeteningagents, flavoring agents, coloring agents and preserving agents in orderto provide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with other non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid, or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in U.S. Pat. Nos. 4,256,108,4,160,452, and 4,265,874 to form osmotic therapeutic tablets for controlrelease.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate, or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxy-ethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil, orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin, or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose, any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The pharmaceutical compositions may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials include, for example, cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions, or suspensions,etc., containing the compounds of the invention are employed. As usedherein, topical application is also meant to include the use ofmouthwashes and gargles.

The compounds of the invention can be administered to provide systemicdistribution of the compound within the patient. Therefore, in someembodiments, the compounds of the invention are administered to producea systemic effect in the body.

As indicated above, the compounds of the invention may be administeredvia oral, mucosal (including sublingual, buccal, rectal, nasal, orvaginal), parenteral (including subcutaneous, intramuscular, bolusinjection, intra-arterial, or intravenous), transdermal, or topicaladministration. In some embodiments, the compounds of the invention areadministered via mucosal (including sublingual, buccal, rectal, nasal,or vaginal), parenteral (including subcutaneous, intramuscular, bolusinjection, intra-arterial, or intravenous), transdermal, or topicaladministration. In other embodiments, the compounds of the invention areadministered via oral administration. In still other embodiments, thecompounds of the invention are not administered via oral administration.

Different therapeutically effective amounts may be applicable fordifferent conditions, as will be readily known by those of ordinaryskill in the art. Similarly, amounts sufficient to treat or prevent suchconditions, but insufficient to cause, or sufficient to reduce, adverseeffects associated with conventional therapies are also encompassed bythe above described dosage amounts and dose frequency schedules.

The compound of the invention, the pharmaceutically acceptable saltthereof, the tautomer thereof, the pharmaceutically acceptable salt ofthe tautomer, the stereoisomer of any of the foregoing, or the mixturethereof may find use in treating a number of conditions. For example, insome embodiments, the invention comprises methods or uses that includethe use or administration of the compound, the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof of the invention, in treating asubject suffering from a cardiovascular condition. In some embodiments,the cardiovascular condition includes, but is not limited to, coronaryheart disease, stroke, heart failure, systolic heart failure, diastolicheart failure, diabetic heart failure, heart failure with preservedejection fraction, heart failure with reduced ejection fraction,cardiomyopathy, myocardial infarction, myocardial remodeling aftercardiac surgery, valvular heart disease, hypertension including,essential hypertension, pulmonary hypertension, portal hypertension,systolic hypertension, aortic aneurysm such as abdominal aorticaneurysm, or atrial fibrillation including improving arrhythmia. In someembodiments, the cardiovascular condition is heart failure. In some suchembodiments, the heart failure is heart failure with reduced ejectionfraction whereas in other embodiments it is heart failure with preservedejection fraction. In other such embodiments the subject may havesystolic heart failure or chronic diastolic heart failure and is thususeful in treating heart failure patients with systolic dysfunction andin treating heart failure patients with diastolic dysfunction. In someembodiments, the cardiovascular condition may be acute heart failurewhereas in other embodiments, the cardiovascular condition ishypertension.

As noted, the compounds of the invention may be used to treat a numberof diseases and disorders. Thus, in some embodiments, the inventionprovides a method of treating a disease or disorder selected from acutedecompensated heart failure, chronic heart failure, pulmonaryhypertension, atrial fibrillation, Brugada syndrome, ventriculartachycardia, atherosclerosis, hypertension, restenosis, ischemiccardiovascular diseases, cardiomyopathy, cardiac fibrosis, arrhythmia,water retention, diabetes, gestational diabetes, obesity, peripheralarterial disease, cerebrovascular accidents, transient ischemic attacks,traumatic brain injuries, amyotrophic lateral sclerosis, burn injuries,sunburn, edema, and preeclampsia in a subject. Such methods includeadministering a compound of the invention, a pharmaceutically acceptablesalt thereof, a tautomer thereof, a pharmaceutically acceptable salt ofthe tautomer, a stereoisomer of any of the foregoing, a mixture thereof,or a pharmaceutical composition that includes any of these to a subjectin need thereof.

In some embodiments, the invention provides a method of improvingcardiac contractility in a subject suffering from a cardiovascularcondition which includes administration of the compound, thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof of the invention to thesubject. The improvement in cardiac contraction may lead to significantimprovements in methods for treating heart failure patients.

In some embodiments, the invention provides a method of improvingcardiac relaxation in a subject suffering from a cardiovascularcondition which includes administration of the compound, thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof of the invention to thesubject. The improvement in cardiac relaxation may lead to significantimprovements in methods for treating heart failure patients.

In some embodiments, the invention provides a method of improvingventricular arterial coupling in a subject suffering from acardiovascular condition which includes administration of the compound,the pharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof of the invention to thesubject. The improvement in ventricular arterial coupling may lead tosignificant improvements in methods for treating heart failure patients.

In some embodiments, the invention provides a method of increasingejection fraction in a subject suffering from a cardiovascular conditionwhich includes administration of the compound, the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof of the invention to the subject.

The compounds of the invention may also find potential benefit inimproving cardiac relaxation and thus find utility in treating certainheart failure patients. The compounds of the invention may thus findutility in improving inotropic function in some embodiments and may alsofind utility in improving lusitropic function.

In some embodiments, the invention provides a method of treatingcondition in a subject where it is desired to activate the APJ Receptor.Such methods include administration of the compound, thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof of the invention to thesubject. In some such embodiments, the condition is obesity or diabeteswhereas in other embodiments, the condition is diabetic nephropathy orchronic kidney disease. In some such embodiments, the condition is typeII diabetes. In other embodiments, the condition is cardiac wasting.

The compounds of the invention may find utility in treating a number ofother conditions. For example, the compounds of the invention may findutility in treating patients with conditions related to renal perfusion,hyperglycemia, aquaresis, and diuresis. In some embodiments, theinvention provides a method of treating one of these subjects thatincludes administration of the compound, the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof of the invention to the subject. The compounds of theinvention may further find utility in arginine vasopressin (AVP)regulation and in angiotensin receptor (AT1R) regulation.

The compounds of the invention may find utility in treating a number ofother conditions or producing desired outcomes or results. For example,the compounds of the invention may find utility in activating stemcells, more specifically cardiac stem cells, and even more specificallyendogenous cardiac stem cells. Thus, the compounds of the invention mayfind utility in activating heart stem cells in a subject such as in ahuman patient. The compounds of the invention may yet further findutility in regrowing tissue and in assisting functional recovery aftertransplanting cells such as cells with bone marrow-derived mesenchymalstem cells. The compounds of the invention may also find utility inincreasing cardiac stem cell proliferation and may be used to do such inpatients that have suffered a myocardial infarction. As another example,the compounds of the invention may find utility in reducing infarctsize, in promoting cardiac repair, and in activating stem cells andprogenitors in post-myocardial infarction subjects. As still yet anotherexample, the compounds of the invention may be used during surgery suchas heart bypass surgery or heart transplant procedures as a therapeuticto reduce reperfusion injury. In some embodiments, the inventionprovides a method of treating one of these subjects or improving thecondition in a subject that includes administration of the compound, thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof of the invention to thesubject.

Some methods of the invention comprise the administration of a compoundof the invention and an additional therapeutic agent (i.e., atherapeutic agent other than a compound of the invention). Thus, thecompounds of the invention can be used in combination with at least oneother therapeutic agent. Examples of additional therapeutic agentsinclude, but are not limited to, antibiotics, anti-emetic agents,antidepressants, antifungal agents, anti-inflammatory agents,antineoplastic agents, antiviral agents, cytotoxic agents, and otheranticancer agents, immunomodulatory agents, alpha-interferons,β-interferons, alkylating agents, hormones, and cytokines. In oneembodiment, the invention encompasses administration of an additionaltherapeutic agent that is used to treat subjects with chronic heartfailure or hypertension.

As described above some methods of the invention comprise theadministration of a compound of the invention and an additionaltherapeutic agent (i.e., a therapeutic agent other than a compound ofthe invention). In some embodiments, the invention encompassesadministration of an additional therapeutic agent that is used to treatsubjects with chronic heart failure or hypertension. In someembodiments, the invention comprises methods or uses that include theuse of a compound, the pharmaceutically acceptable salt thereof, thetautomer thereof, the pharmaceutically acceptable salt of the tautomer,the stereoisomer of any of the foregoing, or the mixture thereof of theinvention and a therapeutic agent such as, but not limited to, anα-blocker, a β-blocker, an angiotensin converting enzyme (ACE)inhibitor, an angiotensin-receptor blocker (ARB), a calcium channelblocker, a diuretic, an inhibitor of the funny current, a myosinactivator, a neutral endopeptidase (NEP) inhibitor, a vasodilator, analdosterone antagonist, a natriuretic, a saluretic, a centrally actinghypertensive, an aldosterone synthase inhibitor, or an endothelinreceptor antagonist. In some embodiments, the invention comprisesmethods or uses that include the use of a compound, the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof of the invention and a therapeuticagent selected from an α-blocker, a β-blocker, an angiotensin convertingenzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calciumchannel blocker, a diuretic, an inhibitor of the funny current, a myosinactivator, or a neutral endopeptidase (NEP) inhibitor. In some suchembodiments, the invention includes a method that includes administeringa compound of the invention, the pharmaceutically acceptable saltthereof, the tautomer thereof, the pharmaceutically acceptable salt ofthe tautomer, the stereoisomer of any of the foregoing, or the mixturethereof and an additional therapeutic agent such as an angiotensinconverting enzyme (ACE) inhibitor or an angiotensin-receptor blocker(ARB). In some such embodiments, the additional therapeutic agent isthus an angiotensin converting enzyme (ACE) inhibitor whereas in othersit is an angiotensin-receptor blocker (ARB). In other such embodiments,the invention includes a method that includes administering a compoundof the invention, the pharmaceutically acceptable salt thereof, thetautomer thereof, the pharmaceutically acceptable salt of the tautomer,the stereoisomer of any of the foregoing, or the mixture thereof and anadditional therapeutic agent such as a neutral endopeptidase (NEP)inhibitor. In other such embodiments, the invention includes a methodthat includes administering a compound of the invention, thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof and an additionaltherapeutic agent such as an inhibitor of the funny current. In someembodiments, the method of use may include two or more additionaltherapeutic agents. For example, in some embodiments, the invention mayinclude a compound of the invention, the pharmaceutically acceptablesalt thereof, the tautomer thereof, the pharmaceutically acceptable saltof the tautomer, the stereoisomer of any of the foregoing, or themixture thereof and additional therapeutic agents such as an ACEinhibitor and a NEP inhibitor.

Therapeutic agents such as α-blockers may be used in conjunction withthe compounds of the invention. Examples of α-blockers include, but arenot limited to, doxazosin, prazosin, tamsulosin, and terazosin and theirpharmaceutically acceptable salts.

Therapeutic agents such as β-blockers may be used in conjunction withthe compounds of the invention. Examples of β-blockers include, but arenot limited to, acebutolol, acetutolol, atenolol, bisoprol, bupranolol,carteolol, carvedilol, celiprolol, esmolol, mepindolol, metoprolol,nadolol, oxprenolol, penbutolol, pindolol, propranolol, taliprolol, andtheir pharmaceutically acceptable salts.

Calcium channel blockers may also be used as therapeutic agents inconjunctions with the compounds of the present invention. Examples ofcalcium channel blockers, include, but are not limited to,dihydropyridines (DHPs) and non-DHPs. Examples of DHPs include, but arenot limited to, amlodipine, felodipine, isradipine, lacidipine,nicardipine, nifedipine, nigulpidine, nilutipine, nimodiphine,nisoldipine, nitrendipine, nivaldipine, ryosidine, and theirpharmaceutically acceptable salts. Examples of Non-DHPs include, but arenot limited to, anipamil, diltiazem, fendiline, flunarizine, gallpamil,mibefradil, prenylamine, tiapamil, verapamil, and their pharmaceuticallyacceptable salts.

Diuretics may also be used in conjunction with the compounds of thepresent invention. Examples include, but are not limited to, thiazidederivatives such as, but not limited to, amiloride, chlorothalidon,chlorothiazide, hydrochlorthiazide, and methylchlorothiazide andpharmaceutically acceptable salts thereof.

Centrally acting hypertensive agents may also be used in conjunctionwith the compounds of the present invention. Examples, include, but arenot limited to, clonidine, guanabenz, guanfacine, methyldopa, andpharmaceutically acceptable salts thereof.

ACE inhibitors may be used in conjunction with the compounds of thepresent invention. Examples of ACE inhibitors that may be used include,but are not limited to, alaceptril, benazepril, benazaprilat, captopril,ceronapril, cilazapril, delapril, enalapril, analaprilat, fosinopril,Lisinopril, moexipiril, moveltopril, perindopril, quinapril,quinaprilat, ramipril, ramiprilat, spriapril, temocapril, trendolapril,and zofenopril and their pharmaceutically acceptable salts. Examples ofsome dual ACE/NEP inhibitors include, but are not limited toomapatrilat, fasidotril, and fasidotrilat and their pharmaceuticallyacceptable salts.

ARBs may also be used as therapeutic agents in conjunction with thecompounds of the present invention. Examples of ARBs include, but arenot limited to, candesartan, eprosartan, irbesartan, losartan,olmesartan, tasosartan, telmisartan, and valsartan and theirpharmaceutically acceptable salts. Examples of some dual ARB/NEPinhibitors include, but are not limited to combinations of valsartan andsacubitril and their pharmaceutically acceptable salts.

NEP inhibitors may also be used as therapeutic agents in conjunctionwith the compounds of the present invention. An example of a NEPinhibitor includes, but it not limited to, sacubitril and itspharmaceutically acceptable salts.

Aldosterone synthase inhibitors may also be used as therapeutic agentsin combination with the compounds of the present invention. Examples ofaldosterone synthase inhibitors include, but are not limited to,anastrozole, fadrozole, and exemestane and their pharmaceuticallyacceptable salts.

Endothelin antagonists are other therapeutic agents that may be used inconjunction with the compounds of the present invention. Examplesinclude, but are not limited to, bosentan, enrasentan, atrasentan,darusentan, macitentan, sitaxentan, and tezosentan, and theirpharmaceutically acceptable salts.

Inhibitors of the funny current (I_(f)) may also be used in conjunctionwith the compounds of the invention. An example of an inhibitor of thefunny current is ivabradine and its pharmaceutically acceptable salts.

Myosin activators may also be used in conjunction with the compounds ofthe invention. Examples of myosin activators include cardiac myosinactivators.

It will be recognized that for purposes of this application, atherapeutic agent other than one of the present invention includescompounds such as known prodrugs that are converted into the therapeuticagent after administration. For example, a compound withoutantineoplastic activity, but that is converted into an antineoplasticagent in the body after administration, may be administered along with acompound of the invention. As another example, sacubitril is considereda NEP inhibitor for the purposes of this application even though it is aprodrug that is converted into sacubitrilat by de-ethylation viaesterases.

When administered as a combination, the therapeutic agents can beformulated as separate compositions that are administered at the sametime or sequentially at different times, or the therapeutic agents canbe given as a single composition. The phrase “co-therapy” (or“combination-therapy”), in defining use of a compound of the presentinvention and another pharmaceutical agent, is intended to embraceadministration of each agent in a sequential manner in a regimen thatwill provide beneficial effects of the drug combination, and is intendedas well to embrace co-administration of these agents in a substantiallysimultaneous manner, such as in a single capsule having a fixed ratio ofthese active agents or in multiple, separate capsules for each agent.Specifically, the administration of compounds of the present inventionmay be in conjunction with additional therapies known to those skilledin the art in the prevention or treatment of cardiovascular conditions.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the accepted dosage ranges. Compoundsof any of the embodiments described herein may also be administeredsequentially with known agents for use in treating cardiovascularconditions such as heart failure and hypertension when a combinationformulation is inappropriate. The invention is not limited in thesequence of administration as compounds of the invention may beadministered either prior to, simultaneous with, or after administrationof a known therapeutic agent.

The invention is further described by reference to the followingexamples, which are intended to exemplify the claimed invention but notto limit it in any way.

EXAMPLES

Unless otherwise noted, all materials were obtained from commercialsuppliers and were used without further purification. Anhydrous solventswere obtained from Sigma-Aldrich (Milwaukee, Wis.) and used directly.All reactions involving air- or moisture-sensitive reagents wereperformed under a nitrogen or argon atmosphere. Purity was measuredusing Agilent 1100 Series high performance liquid chromatography (HPLC)systems with UV detection at 254 nm and 215 nm (System A: Agilent ZorbaxEclipse XDB-C8 4.6×150 mm, 5 micron, 5 to 100% ACN in H₂O with 0.1% TFAfor 15 min at 1.5 mL/min; System B: Zorbax SB-C8, 4.6×75 mm, 10 to 90%ACN in H₂O with 0.1% formic acid for 12 min at 1.0 mL/min). Silica gelchromatography was generally performed with prepacked silica gelcartridges (Biotage or Teledyne-Isco). ¹H NMR spectra were recorded on aBruker AV-400 (400 MHz) spectrometer or a Varian 400 MHz spectrometer atambient temperature, or the NMR spectra were collected with a BrukerAvance III spectrometer operating at a proton frequency of 500.13 MHzusing a 10 μL Protasis CapNMR flow probe. NMR samples were delivered tothe flow probe using a Protasis One-Minute NMR™ Automation systemcomprised of a Discovery Tower™ Sample Manager and a Waters LiquidHandler made by CTC, Switzerland (Model 2777). All observed protons arereported as parts per million (ppm) downfield from tetramethylsilane(TMS) or another internal reference in the appropriate solventindicated. Data are reported as follows: chemical shift, multiplicity(s=singlet, d=doublet, t=triplet, q=quartet, br=broad, m=multiplet),coupling constants, and number of protons. Low-resolution mass spectral(MS) data were determined on an Agilent 1100 Series LC-MS with UVdetection at 254 nm and 215 nm and a low resonance electrospray mode(ESI).

A wide variety of sulfonamide tails and R⁴ groups can be used tosynthesize compounds of the invention such as those set forth in WO2016/187308 and U.S. Pat. Appl. Pub. No. US 2016/0340336 which arehereby incorporated by reference in their entireties and for allpurposes as if specifically set forth herein. Thus, compounds of thepresent invention may be prepared using any of the R³, R⁴, and Q groupstaught in WO 2016/187308 and U.S. Pat. Appl. Pub. No. US 2016/0340336.

The following Abbreviations are used to refer to various reagents andsolvents:

-   ACN Acetonitrile-   AcOH Acetic Acid-   d day or days-   CV Column volume-   DCM Dichloromethane-   DEA Diethylamine-   DMF N,N-Dimethylformamide-   DMSO Dimethylsulfoxide-   EtOAc Ethyl Acetate-   EtOH Ethanol-   EtOTf: Ethyl triflate or ethyl trifluoromethanesulfonate-   h hour or hours-   IPA Isopropanol-   LAH Lithium aluminum hydride-   min minute or minutes-   MeOH Methanol-   MeOTf: Methyl triflate or methyl trifluoromethanesulfonate-   MS Mass spectrum-   MSA Methane sulfonic acid-   RT Room temperature-   SFC Supercritical fluid chromatography-   TBS t-Butyldimethylsilane-   TBSOTf: t-Butyldimethylsilyl triflate or t-butyldimethylsilyl    trifluoromethanesulfonate-   TEA Triethylamine-   TFA Trifluoroacetic acid-   THF Tetrahydrofuran-   TLC Thin Layer Chromatography

Example 1.0. Preparation of2-(4-chlorophenyl)-N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide

N-(2,6-Dimethoxyphenyl)cyclobutanecarboxamide, Example 1.01

To an ice-cooled solution of 2,6-dimethoxyaniline (Amfinecom Inc., 2.0g, 13.1 mmol) in DCM (65 mL) was added N,N-diisopropylethylamine (6.8mL, 39.2 mmol) followed by cyclobutanecarbonyl chloride (Sigma-Aldrich,1.56 mL, 13.7 mmol) slowly via syringe. The resulting solution waswarmed to RT and stirred for 48 h, then was partitioned between waterand DCM (2×). The combined organic layers were dried over anhydroussodium sulfate and concentrated in vacuo to provide Example 1.01 (2.92g, 95% yield). LCMS-ESI (pos.) m/z: 236.2 (M+H)⁺.

N-(2,6-Dimethoxyphenyl)cyclobutanecarbothioamide, Example 1.02

To a suspension of Example 1.01 (2.92 g, 12.4 mmol) in toluene (41.5 mL)was added Lawesson's reagent (2.76 g, 6.8 mmol). The resulting lightyellow slurry was heated at reflux for 9 h and then was allowed to coolto RT. The reaction was quenched with water and extracted with EtOAc(2×). The combined organic layers were dried over anhydrous magnesiumsulfate and concentrated in vacuo. The residue was purified by silicagel chromatography (eluent: 0-100% EtOAc in hexanes) to provide 1.02(3.12 g, 100% yield) as a yellow solid. LCMS-ESI (pos.pos.) m/z: 252.2(M+H)⁺.

N-(2,6-Dimethoxyphenyl)cyclobutanecarbohydrazonamide, Example 1.03

To a solution of 1.02 (1.80 g, 7.2 mmol) in THF (48 mL) was addedhydrazine hydrate solution (80% solution in water, 2.79 mL, 47.0 mmol)via syringe. The resulting slurry was heated at 60° C. for 30 min andthen was partitioned between brine and EtOAc (3×). The combined organiclayers were dried over anhydrous sodium sulfate and concentrated invacuo. The residue was purified by flash chromatography on neutralalumina (eluent: 0-3% MeOH in DCM) to provide 1.03 (510 mg, 29% yield)as a yellow solid. LCMS-ESI (pos.) m/z: 250.2 (M+H)⁺.

5-Cyclobutyl-4-(2,6-dimethoxyphenyl)-4I-1,2,4-triazol-3-amine, Example1.04

To a solution of 1.03 (373 mg, 1.50 mmol) in EtOH (7.5 mL) was addedcyanogen bromide (5.0 M solution in ACN, 658 μL, 3.30 mmol) slowly viasyringe. The reaction was heated at 70° C. for 4.5 h and then wasquenched with water and concentrated in vacuo. The residue was purifiedby reverse phase preparatory HPLC (Sunfire 5 μM C18 column, eluent:10-60% ACN in water over a 20 min period where both solvents contained0.1% TFA) to provide 1.04 (199 mg, 49% yield) as a white solid. LCMS-ESI(pos.) m/z: 275.2 (M+H)⁺.

2-(4-Chlorophenyl)-N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide,Example 1.0

To a solution of 1.04 (80 mg, 0.29 mmol) and TEA (203 μL, 1.46 mmol) inDCM (2.9 mL) was added 2-(4-chlorophenyl)ethanesulfonyl chloride(Synchem Inc., 91 mg, 0.38 mmol). The reaction was stirred at RTovernight and additional 2-(4-chlorophenyl)ethanesulfonyl chloride (182mg, 0.76 mmol) was added. After stirring for an additional 4 h, thereaction was quenched with a saturated aqueous sodium bicarbonatesolution (10 mL) and brine (10 mL). The mixture was extracted with EtOAc(3×). The combined organic layers were dried over anhydrous magnesiumsulfate and concentrated in vacuo. The residue was purified by reversephase preparatory HPLC (Sunfire 5 μM C18 column, eluent: 20-80% ACN inwater over a 20 min period where both solvents contain 0.1% TFA) toprovide Example 1.0 (5.9 mg, 4% yield) as an off-white solid. ¹H NMR(CDCl₃) δ 7.40 (m, 1H), 7.19-7.26 (m, 2H), 7.02-7.14 (m, 2H), 6.63 (d,2H), 3.74 (s, 3H), 3.74 (s, 3H), 3.16-3.38 (m, 2H), 2.95-3.13 (m, 3H),2.21-2.39 (m, 2H), 1.81-2.10 (m, 4H). LCMS-ESI (pos.) m/z: 477.0 (M+H)⁺.

The compounds set forth in the following table were synthesizedfollowing the procedure in Example 1.0 using the known starting materialas described.

TABLE 1 Example Reagents Structure, Name and Data 2.02,6-dimethoxyaniline (commercially available from Amfinecom) andcyclopentanecarboxylic acid (commercially available from Sigma-Aldrich).

2-(4-chlorophenyl)-N-(5-cyclopentyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide. ¹H NMR (500 MHz, CD₃OD) δ7.48-7.55 (m, 1H), 7.25-7.31 (m, 2H), 7.14-7.20 (m, 2H), 6.83 (d, J =8.56 Hz, 2H), 3.81 (s, 3 H), 3.81 (s, 3H), 3.17-3.23 (m, 2H), 2.95-3.01(m, 2H), 2.63-2.71 (m, 1H), 1.75-1.84 (m, 2H), 1.66-1.75 (m, 4H),1.48-1.59 (m, 2H). LCMS-ESI (pos.) m/z: 491.0 (M + H).

The compounds set forth in the following table were synthesizedfollowing the procedure in Example 42.0 using the known startingmaterial as described.

TABLE 2 Example Reagents Structure, Name and Data 3.0(2S,3R)-3-(5-methylpyrimidin- 2-yl)butane-2-sulfonamide (Example 27.0),5-isothiocyanato- 4,6-dimethoxypyrimidine (Example 28.1), andcyclopropanecarboxylic acid hydrazide(commercially available fromSynthonix Inc.).

(2S,3R)-N-(5-cyclopropyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide. ¹H NMR(400 MHz, CDCl₃) δ 10.92 (br s, 1 H) 8.52 (d, J = 0.73 Hz, 2 H) 8.51 (s,1 H) 4.00 (s, 3 H) 3.99 (s, 3 H) 3.83-3.92 (m, 1 H) 3.68- 3.75 (m, 1 H)2.29 (s, 3 H) 2.05 (s, 1 H) 1.39 (d, J = 7.05 Hz, 3 H) 1.35 (d, J = 7.05Hz, 3 H) 0.92-1.05 (m, 2 H) 0.84-0.91 (m, 2 H). LCMS-ESI (pos.) m/z:475.2 (M + H)⁺. 4.0 (2S,3R)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (Example 27.0), 5-isothiocyanato-4,6-dimethoxypyrimidine (Example 28.1), and cyclobutanecarbohydrazide(commercially available from ChemBridge Corporation).

(2S,3R)-N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide. ¹H NMR(500 MHz, DMSO-d₆) δ 12.93 (br s, 1H), 8.67 (s, 1H), 8.58 (s, 2H), 3.91(m, 6H), 3.63 (dd, J = 3.31, 6.75 Hz, 1H), 3.57 (dd, J = 3.44, 6.94 Hz,1H), 3.17 (t, J = 8.30 Hz, 1H), 2.23 (s, 3H), 2.12-2.21 (m, 2H),1.97-2.06 (m, 2H), 1.88-1.97 (m, 1H), 1.75-1.83 (m, 1H), 1.23 (d, J =7.07 Hz, 3H), 1.08 (d, J = 6.94 Hz, 3H). LCMS-ESI (pos.) m/z: 489.2 (M +H)⁺. 5.0 (2S,3R)-3-(5-methylpyrimidin- 2-yl)butane-2-sulfonamide(Example 27.0), 5-isothiocyanato- 4,6-dimethoxypyrimidine, (Example28.1), and cyclohexanecarbohydrazide (commercially available fromChemBridge Corporation).

(2S,3R)-N-(5-cyclohexyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide. ¹H NMR(400 MHz, CDCl₃) δ 11.05 (br s, 1 H) 8.51 (d, J = 2.28 Hz, 3 H) 3.99 (s,3 H) 3.97 (s, 3 H) 3.85 (quin, J = 6.74 Hz, 1 H) 3.71 (quin, J = 6.79Hz, 1 H) 2.28 (s, 3 H) 2.14 (tt, J = 11.55, 3.07 Hz, 1 H) 1.82-1.96 (m,1 H) 1.77 (d, J = 11.82 Hz, 4H) 1.61-1.70 (m, 1 H) 1.42- 1.59 (m, 2 H)1.37 (d, J = 7.15 Hz, 3 H) 1.33 (d, J = 7.05 Hz, 3 H) 1.09-1.21 (m, 2H). LCMS-ESI (pos.) m/z: 517.2 (M + H)⁺. 6.0(1R,2S)-1-(5-chloropyrimidin- 2-yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5-isothiocyanato- 4,6-dimethoxypyrimidine (Example28.1), and cyclohexanecarbohydrazide (commercially available fromFrontier Scientific Services).

(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-cyclohexyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide. ¹HNMR (500 MHz, CDC1₃) δ 10.68 (br s, 1 H) 8.72 (s, 2 H) 8.53 (s, 1 H)4.94 (d, J = 4.80 Hz, 1 H) 4.02 (s, 3 H) 4.01 (s, 3 H) 3.65-3.76 (m, 1H) 3.33 (s, 3 H) 2.10-2.22 (m, 1 H) 1.78 (m, J = 11.68 Hz, 4 H)1.45-1.71 (m, 4 H) 1.35 (d, J = 7.01 Hz, 3 H) 1.21-1.30 (m, 2 H).LCMS-ESI (pos.) m/z: 553.2 (M + H)⁺. 7.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2- sulfonamide (Example 29.3), 5-isothiocyanato-4,6-dimethoxypyrimidine (Example 28.1), and cyclobutanecarbohydrazide(commercially available from ChemBridge Corporation).

(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide. ¹HNMR (500 MHz, DMSO-d₆) δ 12.61 (br s, 1 H) 9.25 (s, 2 H) 9.00 (s, 1 H)5.10 (d, J = 4.02 Hz, 1 H) 4.27 (s, 3 H) 4.26 (s, 3 H) 3.72-3.81 (m, 1H) 3.50 (s, 2 H) 3.47 (s, 3 H) 2.83 (br s, 1 H) 2.30-2.39 (m, 2 H)2.19-2.29 (m, 1 H) 2.12 (q, J = 9.47 Hz, 1 H) 1.47 (d, J = 7.01 Hz, 3H). LCMS-ESI (pos.) m/z: 525.0 (M + H)⁺.

Example 8.0. Preparation ofN-(4-(2-bromo-6-methoxyphenyl)-5-cyclopentyl-4H-1,2,4-triazol-3-yl)-1-(4-chlorophenyl)methanesulfonamide

N-(2-Bromo-6-methoxyphenyl)cyclopentanecarboxamide, Example 8.1

To a 500 mL round-bottom flask was added 2-bromo-6-methoxyaniline(commercially available from Apollo Scientific Ltd., Manchester, UK,8.60 g, 42.6 mmol) and N,N-diisopropylethylamine (14.81 mL, 85 mmol) inDCM (142 mL). At 0° C. cyclopentanecarbonyl chloride (5.69 mL, 46.8mmol) in DCM (50 mL) was added dropwise via syringe. The reactionmixture was stirred at 0° C.-RT. The reaction mixture was diluted with1.0 N HCl and extracted with DCM. The organic extract was washed with asaturated NaCl solution and dried over Na₂SO₄. The solution was filteredand concentrated in vacuo to the title compound (12 g, 40.2 mmol, 95%yield) as a white solid, which was of >85% purity by ¹H NMR and LCMS.The material was directly used in the next step without purification.LCMS-ESI (pos.), m/z: 298.0 (M+H)⁺.

N-(2-Bromo-6-methoxyphenyl)cyclopentanecarbohydrazonamide, example 8.2

to a 500 ml round-bottom flask was addedn-(2-bromo-6-methoxyphenyl)cyclopentanecarboxamide (11.98 g, 40.2 mmol)and thionyl chloride (50 mL, 685 mmol). The reaction mixture was stirredat 66° C. for 30 mins and then at RT overnight. The reaction mixture wasconcentrated in vacuo to give(Z)—N-(2-bromo-6-methoxyphenyl)cyclopentanecarbimidoyl chloride. Theinitial product was directly used in the next step without purification.

To a cooled 500 mL round-bottom flask at 0° C. containing hydrazine(23.79 mL, 758 mmol) in toluene (95 mL) was added a solution of(Z)—N-(2-bromo-6-methoxyphenyl)cyclopentanecarbimidoyl chloride (12 g,37.9 mmol) in toluene (95 mL). The reaction mixture was then stirred atRT for 20 h. Next, the reaction mixture was diluted with water andextracted with Et₂O. The insoluble solid was removed by filtration. Theorganic extract was washed with a saturated NaHCO₃ solution and brineand then dried over Na₂SO₄. The solution was filtered and concentratedin vacuo to give the title compound (10.2 g, 32.7 mmol, 86% yield). Thematerial was directly used in the next step without purification.LCMS-ESI (pos.), m/z: 312.0 (M+H)⁺.

5-Cyclopentyl-4-(2,6-dibromophenyl)-4H-1,2,4-triazol-3-amine, Example8.3

To a 500 mL round-bottom flask was added Example 8.2 (10.22 g, 32.7mmol) and cyanogen bromide (6.55 mL, 32.7 mmol) in MeOH (149 mL). Thereaction mixture was stirred at 70° C. for 18 h. The reaction was notcomplete. Thus, more cyanogen bromide, (5.0 M in ACN, 6.55 mL, 32.7mmol) was added, and the reaction mixture was stirred at 90° C. for 18h. The solution was allowed to cool to RT and concentrated in vacuo. Thereaction mixture was diluted with a saturated solution of NaHCO₃ andextracted with DCM. The organic extract was washed with a saturatedsolution of NaCl and dried over Na₂SO₄. The solution was filtered andconcentrated in vacuo to give the title compound as a tan glass. Thematerial was absorbed onto a plug of silica gel and purified bychromatography through a Redi-Sep pre-packed silica gel column (220 g,gold), eluting with a gradient of 60% to 100% EtOAc in DCM (w/0.5%saturated NH₃—H₂O and 2% MeOH in EtOAc) and then repurified by elutingwith a gradient of 0% to 40% MeOH in DCM, to provide the title compoundExample 8.3 (3.2 g, 9.49 mmol, 29.0% yield) as tan solid. LCMS-ESI(pos.), m/z: 337.0 (M+H)⁺.

(P)—N-(4-(2-Bromo-6-methoxyphenyl)-5-cyclopentyl-4H-1,2,4-triazol-3-yl)-1-(4-chlorophenyl)methanesulfonamideand(M)-N-(4-(2-bromo-6-methoxyphenyl)-5-cyclopentyl-4H-1,2,4-triazol-3-yl)-1-(4-chlorophenyl)methanesulfonamide,Example 8.0

A glass microwave reaction vessel was charged with Example 8.3 (0.148 g,0.44 mmol) and (4-chloro-phenyl)-methanesulfonyl chloride (0.148 g, 0.66mmol) in pyridine (2.19 mL, 0.44 mmol). The reaction mixture was stirredand heated in a Discover model microwave reactor (CEM, Matthews, N.C.)at 120° C. for 120 min (200 watts, Powermax feature off, ramp time 1min). The reaction mixture was then concentrated in vacuo to give a tansolid. The material was absorbed onto a plug of silica gel and purifiedby chromatography through a Redi-Sep pre-packed silica gel column (12g), eluting with a gradient of 0% to 50% EtOAc in hexanes, to providethe title compound (0.047 g, 0.089 mmol, 20% yield) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ 7.38-7.44 (m, 1H) 7.32-7.38 (m, 3H) 7.25-7.32 (m,2H) 7.05 (dd, J=8.22, 1.17 Hz, 1H) 4.21 (d, J=2.15 Hz, 2H) 3.79-3.96 (m,3H) 3.88 (s, 3H) 2.58 (t, J=7.83 Hz, 1H) 1.64-1.92 (m, 6H) 1.48-1.63 (m,2H). LCMS-ESI (pos.) m/z: 524.9 527.0.

Example 9.0. Preparation of1-(4-chlorophenyl)-N-(5-cyclopentyl-4-(2,6-dibromophenyl)-4H-1,2,4-triazol-3-yl)methanesulfonamide

5-Cyclopentyl-4-(2,6-dibromophenyl)-4H-1,2,4-triazol-3-amine, Example9.1

The title compound was prepared from 2,6-dibromoaniline andcyclopentanecarbonyl chloride using the procedures described in Example8.3. LCMS-ESI (pos.), m/z: 386.9 (M+H)⁺.

1-(4-Chlorophenyl)-N-(5-cyclopentyl-4-(2,6-dibromophenyl)-4H-1,2,4-triazol-3-yl)methanesulfonamide,Example 9.0

The title compound was prepared from Example 9.1 using the proceduredescribed in Example 8.0. ¹H NMR (400 MHz, CDCl₃) δ 10.39 (br. s., 1H)7.73-7.79 (m, 2H) 7.26-7.40 (m, 5H) 4.22 (s, 2H) 2.59 (quin, J=7.97 Hz,1H) 1.52-1.92 (m, 8H). LCMS-ESI (pos.) m/z: 572.8, 574.8 and 576.8.

Example 10.0. Preparation of(P)—N-(4-(2-bromo-6-methoxyphenyl)-5-cyclopentyl-4H-1,2,4-triazol-3-yl)-2-(4-chlorophenyl)ethanesulfonamideand(M)-N-(4-(2-bromo-6-methoxyphenyl)-5-cyclopentyl-4H-1,2,4-triazol-3-yl)-2-(4-chlorophenyl)ethanesulfonamide

(P)—N-(4-(2-Bromo-6-methoxyphenyl)-5-cyclopentyl-4H-1,2,4-triazol-3-yl)-2-(4-chlorophenyl)ethanesulfonamideand(M)-N-(4-(2-bromo-6-methoxyphenyl)-5-cyclopentyl-4H-1,2,4-triazol-3-yl)-2-(4-chlorophenyl)ethanesulfonamide,Example 10.0

To a 10 mL vial containing Example 8.3 (106 mg, 0.32 mmol) and TEA (88μL, 0.63 mmol) in DCM (3.1 mL) was added2-(4-chlorophenyl)ethanesulfonyl chloride (83 mg, 0.35 mmol) at RT. Thereaction mixture was stirred at RT for 96 h. The reaction mixture wasdiluted with water and extracted with DCM. The organic extracts werewashed with a saturated NaCl solution and dried over Na₂SO₄. Thesolution was filtered and concentrated in vacuo to give a tan oil. Theinitial material was absorbed onto a plug of silica gel and purified bychromatography through a Redi-Sep pre-packed silica gel column (12 g),eluting with a gradient of 0% to 100% EtOAc in hexanes, to provideExample 10.0 (40 mg, 0.074 mmol, 24% yield) as an off-white solid. ¹HNMR (400 MHz, CDCl₃) δ 10.58 (br. s, 1H) 7.22-7.35 (m, 2H) 7.14-7.22 (m,2H) 7.03 (d, J=7.67 Hz, 2H) 6.94 (dd, J=8.31, 1.27 Hz, 1H) 3.73-3.76 (m,3H) 3.09-3.21 (m, 2H) 2.96-3.05 (m, 2H) 2.46-2.60 (m, 1H) 1.58-1.83 (m,6H) 1.40-1.50 (m, 2H). LCMS-ESI (pos.), m/z: 538.8 (M+H)⁺.

Example 11.0. Preparation of2-(4-chlorophenyl)-N-(5-cyclopentyl-4-(2,6-dibromophenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide

2-(4-Chlorophenyl)-N-(5-cyclopentyl-4-(2,6-dibromophenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide,Example 11.0

The title compound was prepared from Example 9.1 using the proceduredescribed in Example 10.0. ¹H NMR (400 MHz, CDCl₃) δ 10.61 (br. s., 1H)7.66 (d, J=8.02 Hz, 2H) 7.10-7.30 (m, 3H) 7.03 (d, J=6.33 Hz, 2H)3.09-3.25 (m, 2H) 2.93-3.09 (m, 2H) 2.53 (quin, J=7.97 Hz, 1H) 1.63-1.87(m, 6H) 1.50 (br. s., 2H). LCMS-ESI (pos.), m/z: 586.8, 589.0 and 590.9.

Example 12.0. Preparation ofN-(4-(5-bromo-2-methoxyphenyl)-5-cyclopentyl-4H-1,2,4-triazol-3-yl)-2-(4-chlorophenyl)ethanesulfonamide

4-(5-Bromo-2-methoxyphenyl)-5-cyclopentyl-4H-1,2,4-triazol-3-amine,Example 12.1

The title compound was prepared from 5-bromo-2-methoxyaniline andcyclopentanecarbonyl chloride using the procedures described in Example8.3. LCMS-ESI (pos.), m/z: 337.0 339.0.

N-(4-(5-Bromo-2-methoxyphenyl)-5-cyclopentyl-4H-1,2,4-triazol-3-yl)-2-(4-chlorophenyl)ethanesulfonamide,Example 12.0

The title compound was prepared from Example 12.1 using the proceduredescribed in Example 10.0. ¹H NMR (400 MHz, CDCl₃) δ 7.52 (dd, J=8.90,2.45 Hz, 1H) 7.15-7.22 (m, 3H) 6.99-7.06 (m, 2H) 6.86 (d, J=8.80 Hz, 1H)3.70 (s, 3H) 3.13-3.22 (m, 2H) 2.92-3.02 (m, 2H) 2.57 (d, J=7.82 Hz, 1H)1.31-1.78 (m, 8H). LCMS-ESI (pos.), m/z: 539.0 541.0.

Example 13.0. Preparation of2-(4-chlorophenyl)-N-(4-(2-(difluoromethoxy)phenyl)-5-(5-fluoro-2-thiophenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide

5-Cyclopentyl-4-(2-methoxyphenyl)-4H-1,2,4-triazol-3-amine, Example 13.1

To a 150 mL round-bottom flask was added Example 12.1 (0.2 g, 0.593mmol) in EtOH (30 mL). The solution was flushed with N₂. Palladium onactivated carbon (10% Pd, 0.063 g, 0.59 mmol) was added under N₂. Theflask was closed with a septum and the system was placed under vacuum.The reaction mixture was then stirred at RT under an atmosphere ofhydrogen gas for 2 h. The mixture was filtered through a silica gel pad,rinsed with MeOH and concentrated in vacuo to give the initial materialExample 13.1 as a tan glass, which was directly used in the next stepwithout further purification. LCMS-ESI (pos.), m/z: 259.1 (M+H)⁺.

2-(4-Chlorophenyl)-N-(4-(2-(difluoromethoxy)phenyl)-5-(5-fluoro-2-thiophenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide,Example 13.0

The title compound was prepared from Example 13.1 using the proceduredescribed in Example 10.0. ¹H NMR (400 MHz, CDCl₃) δ 10.62 (br. s., 1H)7.52 (t, J=7.84 Hz, 1H) 7.23-7.29 (m, 2H) 7.20 (dd, J=7.73, 1.66 Hz, 1H)7.06-7.15 (m, 4H) 3.81 (s, 3H) 3.22-3.30 (m, 2H) 3.03-3.12 (m, 2H) 2.69(t, J=7.83 Hz, 1H) 1.48-1.87 (m, 8H). LCMS-ESI (pos.), m/z: 461.0(M+H)⁺.

Example 14.0. Preparation of(P)—N-(4-(2-bromo-6-methoxyphenyl)-5-cyclopentyl-4H-1,2,4-triazol-3-yl)-2-(4-chlorophenyl)ethanesulfonamideor(M)-N-(4-(2-bromo-6-methoxyphenyl)-5-cyclopentyl-4H-1,2,4-triazol-3-yl)-2-(4-chlorophenyl)ethanesulfonamide

(P)—N-(4-(2-Bromo-6-methoxyphenyl)-5-cyclopentyl-4H-1,2,4-triazol-3-yl)-2-(4-chlorophenyl)ethanesulfonamideor(M)-N-(4-(2-bromo-6-methoxyphenyl)-5-cyclopentyl-4H-1,2,4-triazol-3-yl)-2-(4-chlorophenyl)ethanesulfonamide,Example 14.0

Example 14.0 was the first isomer to elute under the followingconditions to separate the racemic compound Example 10.0. 250×30 mmLux-2 column with 44 g/min MeOH (20 mM NH₃)⁺36 g/min CO₂ on Thar 80 SFC.Outlet pressure=100 bar; Temp.=29° C.; Wavelength=220 nm. Used 1.5 mLinjections of 50 mg/10 mL (5 mg/mL) sample solution in MeOH, i.e. 7.5mg/injection. Run time=18 min, Cycle time=10 min. ¹H NMR (400 MHz,CDCl₃) δ 10.62 (br. s, 1H) 7.14-7.33 (m, 4H) 7.03 (d, J=7.74 Hz, 2H)6.94 (dd, J=8.31, 1.08 Hz, 1H) 3.73-3.77 (m, 3H) 3.11-3.23 (m, 2H)2.97-3.05 (m, 2H) 2.52 (quin, J=7.87 Hz, 1H) 1.57-1.83 (m, 6H) 1.39-1.56(m, 2H). LCMS-ESI (pos.), m/z: 539.0 541.0.

Example 15.0. Preparation of(P)—N-(4-(2-bromo-6-methoxyphenyl)-5-cyclopentyl-4H-1,2,4-triazol-3-yl)-2-(4-chlorophenyl)ethanesulfonamideor(M)-N-(4-(2-bromo-6-methoxyphenyl)-5-cyclopentyl-4H-1,2,4-triazol-3-yl)-2-(4-chlorophenyl)ethanesulfonamide

(P)—N-(4-(2-Bromo-6-methoxyphenyl)-5-cyclopentyl-4H-1,2,4-triazol-3-yl)-2-(4-chlorophenyl)ethanesulfonamideor(M)-N-(4-(2-bromo-6-methoxyphenyl)-5-cyclopentyl-4H-1,2,4-triazol-3-yl)-2-(4-chlorophenyl)ethanesulfonamide,Example 14.0

Example 15.0 is the enantiomer of Example 14.0. The title compoundExample 15.0 was the second isomer to elute on subjecting Example 10.0to the SFC conditions described in Example 14.0. ¹H NMR (400 MHz, CDCl₃)δ 10.74 (br. s, 1H) 7.31-7.43 (m, 2H) 7.25-7.31 (m, 2H) 7.13 (d, J=7.26Hz, 2H) 7.04 (dd, J=8.22, 1.17 Hz, 1H) 3.84 (s, 3H) 3.19-3.32 (m, 2H)3.07-3.14 (m, 2H) 2.62 (t, J=7.83 Hz, 1H) 1.69-1.92 (m, 6H) 1.50-1.62(m, 2H). LCMS-ESI (pos.), m/z: 539.0, 541.0.

Example 16.0: Preparation of(1R,2S)—N-(5-cyclopropyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide

(E)-N′-(2,6-Dimethoxyphenyl)-N-(((1R,2S)-1-methoxy-1-(5-methylpyrimidin-2-yl)propan-2-yl)sulfonyl)carbamimidothioicacid, Example 16.1

Example 29.0 (0.203 g, 0.83 mmol) was suspended in ACN (8 mL) in a vial.The vial was warmed in a warm water bath to give a clear solution. Tothe solution, at RT, was added 28.0 (0.168 g, 0.859 mmol) followed byportion-wise addition of cesium carbonate (0.37 g, 1.13 mmol). Theslightly cloudy mixture was stirred at RT for 15 h to obtain asuspension. LCMS-ESI (pos.) m/z: 440.9 (M+H)⁺. This suspension of 16.1was used as 0.1 M stock solution.

(1R,2S)—N-(5-Cyclopropyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide,Example 16.0

To a 20 mL scintillation vial was added 16.1 (2.50 mL, 0.250 mmol) andcyclopropanecarbohydrazide (0.025 g, 0.25 mmol, Frontier ScientificServices, Inc., Newark, Del.). The mixture was cooled in an ice-waterbath and silver(I) nitrate (0.085 g, 0.50 mmol) was added. The cold bathwas removed, and the brown mixture was stirred at RT. After 15 min, themixture was filtered through a pad of diatomaceous earth (flushing withACN). The filtrate was concentrated in a GeneVac into a 20 mLscintillation vial. Dioxane (2 mL) was added to the yellow residuefollowed by MSA (0.073 g, 0.76 mmol). The mixture was stirred at 80° C.for overnight. The reaction mixture was then allowed to cool to RT andconcentrated in vacuo. The residue was dissolved in MeOH (˜2 mL) and themixture was passed through a PS-carbonate column, eluting with MeOH. Thefiltrate was concentrated in vacuo and purified by mass-triggered HPLCto afford 16.0 (0.082 g, 0.11 mmol, 67% yield). ¹H NMR (500 MHz,DMSO-d₆) δ 12.57 (br. s., 1H), 8.64 (s, 2H), 7.50 (t, J=8.50 Hz, 1H),6.86 (dd, J=1.39, 8.53 Hz, 2H), 4.79 (d, J=3.50 Hz, 1H), 3.76 (m, 6H),3.34-3.42 (m, 1H), 3.14 (s, 3H), 2.26 (s, 3H), 1.27-1.36 (m, 1H), 1.11(d, J=7.01 Hz, 3H), 0.73-0.83 (m, 4H). LCMS (pos.) m/z: 489.1 (M+H)⁺.

The compounds set forth in the following table were synthesizedfollowing the procedure in Example 16.0 using the known startingmaterial as described.

TABLE 3 17.0 (2S,3R)-3-(5-methylpyrimidin-2- yl)butane-2-sulfonamide(Example 27.0), cyclopentanecarbohydrazide (commercially available fromMatrix Scientific), and 2-isothiocyanato-1,3- dimethoxybenzene (Example28.0).

(2S,3R)-N-(5-cyclopentyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide. ¹H NMR (400 MHz, CD₂Cl₂) δ0.90 (br. s., 1H), 8.50 (d, J = 0.6 Hz, 2H), 7.51-7.43 (m, 1H),6.75-6.68 (m, 2H), 3.80 (s, 3H), 3.78 (s, 3H), 3.76-3.69 (m, 1H),3.67-3.59 (m, 1H), 2.69-2.59 (m, 1H), 2.26 (s, 3H), 1.84-1.65 (m, 6H),1.57-1.46 (m, 2H), 1.30 (d, J = 7.0 Hz, 3H), 1.25 (d, J = 7.0 Hz, 3H).LCMS-ESI (pos.), m/z: 501.2 (M + H)⁺. 18.0(2S,3R)-3-(5-methylpyrimidin-2- yl)butane-2-sulfonamide (Example 27.0),cyclopentanecarbohydrazide (commercially available from MatrixScientific), and 5-isothiocyanato-4,6- dimethoxypyrimidine (Example28.1).

(2S,3R)-N-(5-cyclopentyl-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2- sulfonamide. ¹H NMR (400 MHz,CD₂Cl₂) δ 10.95 (br. s., 1H), 8.56-8.52 (m, 1H), 8.52-8.48 (m, 2H), 3.99(s, 3H), 3.98 (s, 3H), 3.78-3.70 (m, 1H), 3.67-3.58 (m, 1H), 2.70-2.59(m, 1H), 2.26 (s, 3H), 1.82-1.67 (m, 6H), 1.60-1.49 (m, 2H), 1.31 (d, J= 7.0 Hz. 3H), 1.26 (d, J = 6.8 Hz, 3H), LCMS-ESI (pos.), m/z: 503.2(M + H)⁺. 19.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2-sulfonamide (Example 29.3), cyclopentanecarbohydrazide(commercially available from Matrix Scientific), and5-isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1)

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-cyclopentyl-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide. ¹H NMR (400 MHz,CD₂Cl₂) δ 10.78 (br. s., 1H), 8.75-8.69 (m, 2H), 8.58-8.51 (m, 1H), 4.88(d, J = 4.6 Hz, 1H), 4.02 (s, 3H), 4.00 (s, 3H), 3.57 (dq, J = 4.5, 7.0Hz, 1H), 3.29-3.23 (m, 3H), 2.71-2.60 (m, 1H), 1.83-1.75 (m, 4H),1.74-1.65 (m, 2H), 1.60-1.49 (m, 2H), 1.25 (d, J = 7.0 Hz, 3H). LCMS-ESI(pos.), m/z: 539.2 (M + H)⁺. 20.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2-sulfonamide (Example 29.3), (S)-2,2-dimethylcyclopropane- carbohydrazide hydrochloride and (R)-2,2-dimethylcyclopropane- carbohydrazide hydrochloride (commerciallyavailable from Chembridge), and 4- isothiocyanatooxane (commerciallyavailable from Oakwood Products Inc.). The mixture obtained was purifiedby preparative SFC method: Column: AD-H (2 × 25 cm) Mobile Phase: 60:40(A:B) A: Liquid CO₂, B: MeOH, Flow Rate: 80 mL/min, 220 nm, 100 barinlet pressure to deliver Peak 1.

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((R)-2,2-dimethylcyclopropyl)-4-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)-1- methoxypropane-2-sulfonamide or(1R,2S)-1- (5-chloropyrimidin-2-yl)-N-(5-((S)-2,2-dimethylcyclopropyl)-4-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)-1- methoxypropane-2-sulfonamide. ¹H NMR(500 MHz, DMSO-d₆) δ 12.60 (br s, 1H), 8.94 (s, 2H), 4.91 (d, J = 3.6Hz, 1H), 4.30 (tt, J = 3.8, 12.2 Hz, 1H), 4.00 (d, J = 11.4 Hz, 2H),3.47-3.36 (m, 3H), 3.09 (s, 3H), 2.49- 2.42 (m, 2H), 1.97 (dd, J = 5.6,8.4 Hz, 1H), 1.74 (d, J = 11.2 Hz, 1H), 1.62 (d, J = 11.2 Hz, 1H),1.27-1.21 (m, 6H), 1.09 (t, J = 4.9 Hz, 1H), 0.94 (dd, J = 4.4, 8.3 Hz,1H), 0.85 (s, 3H). LCMS-ESI (pos.), m/z: 485.2 (M + H)⁺. 21.0(1R,2S)-1-(5-chloropyrimidin-2-yl)-1- methoxypropane-2-sulfonamide(Example 29.3), (S)-2,2- dimethylcyclopropanecarbohydrazidehydrochloride and (R)-2,2- dimethylcyclopropanecarbohydrazidehydrochloride (commercially available from Chembridge), and 4-isothiocyanatooxane (commercially available from Oakwood Products Inc.).The mixture obtained was purified by preparative SFC method: Column: AD-H (2 × 25 cm) Mobile Phase: 60:40 (A:B) A: Liquid CO₂, B: MeOH, FlowRate: 80 mL/min, 220 nm, 100 bar inlet pressure to deliver Peak 2.

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((R)-2,2-dimethylcyclopropyl)-4-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)-1- methoxypropane-2-sulfonamide or(1R,2S)-1- (5-chloropyrimidin-2-yl)-N-(5-((S)-2,2-dimethylcyclopropyl)-4-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)-1- methoxypropane-2-sulfonamide. ¹H NMR(500 MHz, DMSO-d₆) δ 12.59 (br s, 1H), 8.92 (s, 2H), 4.90 (d, J = 3.9Hz, 1H), 4.25 (t, J = 12.1 Hz, 1H), 4.04-3.95 (m, 2H), 3.51- 3.45 (m,1H), 3.43-3.36 (m, 2H), 3.12 (s, 3H), 2.50-2.45 (m, 2H), 1.96 (dd, J =5.4, 8.0 Hz, 1H), 1.71 (d, J = 11.4 Hz, 1H), 1.57 (d, J = 11.4 Hz, 1H),1.29-1.22 (m, 6H), 1.08 (t, J = 4.7 Hz, 1H), 0.94 (dd, J = 4.3, 8.4 Hz,1H), 0.91- 0.83 (m, 3H). LCMS-ESI (pos.), m/z: 485.2 (M + H)⁺. 22.0(1R,2S)-1-(5-chloropyrimidin-2-yl)-1- methoxypropane-2-sulfonamide(Example 29.3), (S)-2,2- dimethylcyclopropanecarbohydrazidehydrochloride and (R)-2,2- dimethylcyclopropanecarbohydrazidehydrochloride (commercially available from Chembridge), and 2-isothiocyanato-1,3-dimethoxybenzene (Example 28.0). The mixture waspurified by preparative SFC method: Column: AD- H (2 × 25 cm) MobilePhase: 75:25 (A:B) A: Liquid CO₂, B: MeOH, Flow Rate: 60 mL/min, 215 nm,100 bar inlet pressure to deliver Peak 1.

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((R)-2,2-dimethylcyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((S)-2,2-dimethylcyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 12.61 (br s,1H), 8.93 (s, 2H), 7.51 (t, J = 8.4 Hz, 1H), 6.87 (dd, J = 3.4, 8.3 Hz,2H), 4.79 (d, J = 4.2 Hz, 1H), 3.77 (s, 3H), 3.76-3.72 (m, 3H), 3.42-3.34 (m, 1H), 3.14 (s, 3H), 1.14 (d, J = 7.0 Hz, 3H), 1.12-1.08 (m, 1H),1.01 (t, J = 4.9 Hz, 1H), 0.89 (s, 3H), 0.87-0.83 (m, 4H). LCMS- ESI(pos.), m/z: 537.2 (M + H)⁺. 23.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2-sulfonamide (Example 29.3), (S)-2,2-dimethylcyclopropanecarbohydrazide hydrochloride and (R)-2,2-dimethylcyclopropanecarbohydrazide hydrochloride (commercially availablefrom Chembridge), and 2- isothiocyanato-1,3-dimethoxybenzene (Example28.0). The mixture was purified by preparative SFC method: Column: AD- H(2 × 25 cm) Mobile Phase: 75:25 (A:B) A: Liquid CO₂, B: MeOH, Flow Rate:60 mL/min, 215 nm, 100 bar inlet pressure to deliver Peak 2.

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((R)-2,2-dimethylcyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((S)-2,2-dimethylcyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 12.64 (br s,1H), 8.92 (s, 2H), 7.51 (t, J = 8.4 Hz, 1H), 6.87 (d, J = 8.6 Hz, 2H),4.80 (d, J = 4.4 Hz, 1H), 3.77 (s, 3H), 3.76 (s, 3H), 3.44-3.35 (m, 1H),3.14 (s, 3H), 1.14 (d, J = 7.0 Hz, 3H), 1.12-1.08 (m, 1H), 1.01 (t, J =4.9 Hz, 1H), 0.91 (s, 3H), 0.88- 0.82 (m, 4H). LCMS-ESI (pos.), m/z:537.2 (M + H)⁺. 24.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2-sulfonamide (Example 29.3), cyclopropanecarboxylic acidhydrazide (commercially available from Enamine), and5-isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-cyclopropyl-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ 12.83 (s, 1H), 8.93 (s, 2H), 8.70 (s, 1H), 4.77 (d, J = 4.1Hz, 1H), 4.00-3.97 (m, 3H), 3.97-3.95 (m, 3H), 3.43-3.36 (m, 1H), 3.13(s, 3H), 1.58- 1.51 (m, 1H), 1.14 (d, J = 6.8 Hz, 3H), 0.88- 0.78 (m,4H). LCMS-ESI (pos.), m/z: 511.0 (M + H)⁺. 25.0(1R,2S)-1-(5-chloropyrimidin-2-yl)-1- methoxypropane-2-sulfonamide(Example 29.3), (S)-2,2- dimethylcyclopropanecarbohydrazidehydrochloride and (R)-2,2- dimethylcyclopropanecarbohydrazidehydrochloride (commercially available from Chembridge), and 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1). The mixture waspurified by preparative SFC method: Column: AD- H (2 × 25 cm) MobilePhase: 70:30 (A:B) A: Liquid CO₂, B: IPA. Flow Rate: 90 mL/min, 220 nm,100 bar inlet pressure to deliver Peak 1.

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((R)-2,2-dimethylcyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6- dimethoxypyrimidin-5-yl)-5-((S)-2,2-dimethylcyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 12.86 (s, 1H),8.93 (s, 2H), 8.70 (s, 1H), 4.80 (d, J = 3.9 Hz, 1H), 4.01-3.98 (m, 3H),3.98-3.96 (m, 3H), 3.43-3.36 (m, 1H), 3.13 (s, 3H), 1.36 (dd, J = 5.1,8.6 Hz, 1H), 1.14 (d, J = 6.7 Hz, 3H), 1.04 (t, J = 5.1 Hz, 1H),0.97-0.94 (m, 3H), 0.93-0.91 (m, 3H), 0.90-0.87 (m, 1H). LCMS-ESI(pos.), m/z: 539.2 (M + H)⁺. 26.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2-sulfonamide (Example 29.3), (S)-2,2-dimethylcyclopropanecarbohydrazide hydrochloride and (R)-2,2-dimethylcyclopropanecarbohydrazide hydrochloride (commercially availablefrom Chembridge), and 5- isothiocyanato-4,6- dimethoxypyrimidine(Example 28.1). The mixture was purified by preparative SFC method:Column: AD- H (2 × 25 cm) Mobile Phase: 70:30 (A:B) A: Liquid CO₂, B:IPA, Flow Rate: 90 mL/min, 220 nm, 100 bar inlet pressure to deliverPeak 2.

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((R)-2,2-dimethylcyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6- dimethoxypyrimidin-5-yl)-5-((S)-2,2-dimethylcyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 12.84 (s, 1H),8.93 (s, 2H), 8.70 (s, 1H), 4.79 (d, J = 3.9 Hz, 1H), 4.00-3.97 (m, 3H),3.97-3.96 (m, 3H), 3.42-3.35 (m, 1H), 3.13 (s, 3H), 1.36 (dd, J = 5.6,8.4 Hz, 1H), 1.14 (d, J = 7.0 Hz, 3H), 1.04 (t, J = 5.1 Hz, 1H),0.97-0.93 (m, 3H), 0.93-0.91 (m, 3H), 0.90-0.87 (m, 1H). LCMS-ESI(pos.), m/z: 539.2 (M + H)⁺.

Example 27.0: Preparation of(2S,3R)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide

(E)-2-(But-2-en-2-yl)-5-methylpyrimidine, Example 27.01

2-Chloro-5-methyl-pyrimidine (18 mL, 151 mmol), potassium(Z)-but-2-en-2-yltrifluoroborate (Sigma Aldrich, 31 g, 191 mmol),tricyclohexylphosphine (8.5 g, 30.2 mmol), and Pd₂(dba)₃ (13.82 g, 15.09mmol) were added to a flask which was then degassed and backfilled withnitrogen. To the flask was added 1,4-dioxane (252 mL) and aqueouspotassium phosphate tribasic (37.5 mL, 453 mmol). The resulting reactionwas heated at 100° C. for 16 h. The reaction was then cooled to RT. Theresidue was filtered through a plug of silica gel and then loaded ontosilica gel (0-20% EtOAc in heptanes) to afford(E)-2-(but-2-en-2-yl)-5-methylpyrimidine 27.1 (19 g, 125 mmol, 83%yield).

2-(2-Chloro-3-(pyrimidin-2-ylthio)butan-2-yl)-5-methylpyrimidine,Example 27.02

To a solution of pyrimidine-2-thiol (14.8 g, 132 mmol) in DCM (440 mL)was added sulfuryl chloride (10.73 mL, 132 mmol). The reaction wasstirred at 0° C. for 1 h and a further 1 h at RT. To the cloudy reactionmixture was added (E)-2-(but-2-en-2-yl)-5-methylpyrimidine 27.01 (20 g,132 mmol) dropwise, and the mixture was further stirred for 2 h. Thereaction mixture was concentrated in vacuo. An aqueous sodiumbicarbonate solution was added to the mixture to neutralize the reactionmixture. The reaction was extracted with EtOAc and concentrated invacuo. The residue was purified on silica gel with 0-25% EtOAc inhexanes to give the desired product2-(2-chloro-3-(pyrimidin-2-ylthio)butan-2-yl)-5-methylpyrimidine 27.02(30 g, 76% yield).

2-(2-Chloro-3-(pyrimidin-2-ylsulfonyl)butan-2-yl)-5-methylpyrimidine,Example 27.03

To a solution of2-(2-chloro-3-(pyrimidin-2-ylthio)butan-2-yl)-5-methylpyrimidine 27.02(30 g, 100 mmol) in DCM (201 mL) was added meta-chloroperoxybenzoic acid(45.0 g, 201 mmol). The reaction was stirred at RT for 1 d. The reactionwas concentrated in vacuo and aqueous sodium bicarbonate and sodiumthiosulfate were added. The mixture was extracted with EtOAc andconcentrated in vacuo to give the desired product2-(2-chloro-3-(pyrimidin-2-ylsulfonyl)butan-2-yl)-5-methylpyrimidine27.03 (33.2 g, 100 mmol, 100% yield).

Potassium (E)-3-(5-methylpyrimidin-2-yl)but-2-ene-2-sulfinate, Example27.04

To a solution of2-(2-chloro-3-(pyrimidin-2-ylsulfonyl)butan-2-yl)-5-methylpyrimidine27.03 (33 g, 100 mmol) in MeOH (249 mL) was added potassium carbonate(27.6 g, 200 mmol). The reaction was stirred at RT for 16 h. Thereaction was concentrated in vacuo to give the desired product,potassium (E)-3-(5-methylpyrimidin-2-yl)but-2-ene-2-sulfinate 27.04(21.57 g, 100% yield) which was used without further purification.

(E)-3-(5-Methylpyrimidin-2-yl)but-2-ene-2-sulfonamide, Example 27.05

To a solution of potassium(E)-3-(5-methylpyrimidin-2-yl)but-2-ene-2-sulfinate (Example 27.04,21.57 g, 85 mmol) in water (424 mL, 85 mmol) was added potassium acetate(5.30 mL, 85 mmol) followed by amidoperoxymonosulfuric acid (19.18 g,170 mmol). The reaction was stirred at RT for 24 h. The reaction wasextracted with EtOAc and concentrated in vacuo. The product thusobtained was purified on silica gel eluting with 0-50% EtOAc in hexanesto give the desired product(E)-3-(5-methylpyrimidin-2-yl)but-2-ene-2-sulfonamide 27.05 (12 g, 61%yield).

(2S,3R)-3-(5-Methylpyrimidin-2-yl)butane-2-sulfonamide, Example 27.0

A 900 mL pressure reactor was charged under nitrogen flow with(E)-3-(5-methylpyrimidin-2-yl)but-2-ene-2-sulfonamide, Example 27.05(40.00 g, 0.1760 mol, 1 equiv), zinc trifluoromethane sulfonate (12.79g, 0.0352 mol, 0.2 equiv, Aldrich), bis(1,5-cyclooctadiene)rhodium(I)tetrafluoroborate (1.43 g, 0.00352 mol, 0.02 equiv, Strem Chemicals,Inc.),(S)-1-[(R)-2-(di-1-naphthylphosphino)ferrocenyl]-ethyl-di-tert.-butylphosphine(2.60 g, 0.00405 mol, 0.023 equiv, Solvias) and MeOH (520 mL). Themixture was purged with nitrogen and then with hydrogen and the mediawas stirred under 3-4 bars of hydrogen for 20 h. The reaction wasmonitored by HPLC and showed a complete conversion. The reactor waspurged with nitrogen and the resulting suspension was concentrated at35° C. under industrial vacuum to give initial material as an orangesolid. The initial material was mixed with EtOH (742 mL) and theresulting suspension was stirred at 20-25° C. for 40 mins. The solid wasfiltered, washed with EtOH (2×97 mL) and dried at 40° C. under vacuum togive the title compound as a white powder (85.2% yield, 99% ee). ¹H NMR(400 MHz, DMSO-d₆): δ 8.61 (s, 2H), 6.84 (s, 2H), 3.69 (tt, J=12.4, 4.5Hz, 2H), 2.25 (s, 3H), 1.32 (d, J=6.9 Hz, 3H), 1.20 (d, J=7.0 Hz, 3H).LCMS ESI (pos.) m/z; 230.1 (M+H)⁺.

The compounds in the following table were synthesized following theprocedure in Example 27.0 using the known starting material asdescribed.

TABLE 4 Example Reagents Structure, Name and Data 27.12-chloro-5-fluoro- pyrimidine.

(2S,3R)-3-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide. LCMS ESI (pos.)m/z: 234.2 (M + H)⁺. 27.2 2-bromo-5- methylpyrazine. The title compoundwas the first isomer to elute under the following SFC conditions: Run onThar 200 SFC with 250 × 30 mm AD-H column with 20 mL/min MeOH (+20 mMNH₃) + 80 g/min CO₂, 20% co-solvent at 100 g/min.

Temperature. = 29° C.,(2S,3R)-3-(5-methylpyrazin-2-yl)butane-2-sulfonamide. Outlet pressure =100 ¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (d, J = 6.5 Hz, bar, Wavelength =271 2H), 6.84 (s, 2H), 3.63 (qd, J = 7.0, 4.3 Hz, 1H), 3.44 (qd, nm.Injected 1.0 mL of J = 7.0, 4.3 Hz, 1H), 2.47 (s, 3H), 1.31 (d, J = 7.0Hz, 550 mg of the 3H), 1.23 (d, J = 7.0 Hz, 3H). LCMS-ESI ( pos) m/z;enantiomerically 230.0 (M + H)⁺. enriched product dissolved in 20 mLMeOH:DCM, 15:5; c = 27.5 mg/mL and 27.5 mg per injection. Cycle time 5.0min, run time 13 min. 27.3 2-bromo-5- methylpyrazine. The title compoundis the enantiomer of Example 27.2. Example 27.2 is the second isomer toelute from AD-H column on subjecting the enantiomerically enrichedproduct to the SFC conditions described in Example 27.2.

(2R,3S)-3-(5-methylpyrazin-2-yl)butane-2-sulfonamide. LCMS-ESI (pos.)m/z: 230.0 (M + H)⁺. 27.4 2-chloro-5-chloro- pyrimidine.Recrystallization: Example 1.4 (38 g, 90% ee) was dissolved in IPA (400mL) at 70° C.

(2S,3R)-3-(5-chloropyrimidin-2-yl)butane-2-sulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ 8.93-8.85 (m, 2H), 6.86 (d, J = 4.0 Hz, 2H), 3.73-3.59 (m,2H), 1.31 (dt, J = 7.3, 2.4 Hz, 3H), 1.25-1.19 (m, 3H). LCMS-ESI (pos.)m/z: 250.2 (M + H)⁺. 27.5 2-bromo-5- methoxypyrazine.

(2S,3R)-3-(5-methoxypyrazin-2-yl)butane-2-sulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ 8.26 (d, J = 1.4 Hz, 1H), 8.12 (d, J = 1.4 Hz, 1H), 6.84 (s,2H), 3.90 (d, J = 1.5 Hz, 3H), 3.62 (dd, J = 7.1, 4.3 Hz, 1H), 3.42-3.38(m, 1H), 1.32 (d, J = 1.5 Hz, 3H), 1.23-1.21 (m, 3H). LCMS-ESI (pos.)m/z: 246.2 (M + H)⁺. 27.6 2-chloro-5- methoxypyrimidine.

(2S,3R)-3-(5-methoxypyrimidin-2-yl)butane-2- sulfonamide. LCMS-ESI(pos.) m/z: 246.2 (M + H)⁺.

Example 28.0. Preparation of 2-isothiocyanato-1,3-dimethoxybenzene

2-Isothiocyanato-1,3-dimethoxybenzene, Example 28.0

To a solution of 2,6-dimethoxyaniline (500 g, 3.25 mol, 1 eq) in DCM(5.0 L) was added 2,6-lutidine (1.5 L, 13.0 mol, 4 eq). The reactionmixture was cooled to 0° C. (internal temperature) and CSCl₂ (374 mL,4.88 mol, 1.5 eq) was added drop-wise. The reaction mixture was allowedto stir for 2 h. The solvent was then evaporated in vacuo, and theinitial mass was purified by SiO₂ column to provide2-isothiocyanato-1,3-dimethoxybenzene, Example 28.0 as white solid.LCMS-ESI (pos.) m/z: (M+H)⁺=196. ¹H NMR (400 MHz, CDCl₃) δ 7.16 (t,J=8.48 Hz, 1H), 6.55 (d, J=8.48 Hz, 2H), 3.90 (app s, 6H).

The compounds set forth in the following table were synthesizedfollowing the procedure in Example 28.0 using the known startingmaterial as described.

TABLE 5 Example Reagents Structure, Name and Data 28.14,6-dimethoxypyrimidin- 5-amine (commercially available from D-L Chiralchemicals).

5-isothiocyanato-4,6-dimethoxypyrimidine. LCMS-ESI (pos.) m/z: 198.1(M + H)⁺. 28.2 Commercially available from CombiBlocks.

1-isothiocyanato-2-methoxybenzene. ¹H NMR (400 MHz, DMSO-d₆) δ 3.89 (s,3H), 6.96 (td, J = 7.68, 1.27 Hz, 1H), 7.16 (dd, J = 8.31, 1.27 Hz, 1H),7.30 (dd, J = 7.92, 1.66 Hz, 1H), 7.31-7.37 (m, 1H). 28.33,5-difluoropyridin-4- amine (commercially available from Ark Pharm Inc,Libertyville, IL).

3,5-difluoro-4-isothiocyanatopyridine. LCMS-ESI (pos.) m/z: 173.0 (M +H)⁺.

Example 29.0. Preparation of(1R,2S)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide

(E)-5-Methyl-2-(prop-1-en-1-yl)pyrimidine, Example 29.01

To a 500 mL round bottom flask was added 2-chloro-5-methylpyrimidine (12g, 93 mmol), potassium (E)-trifluoro(prop-1-en-1-yl)borate (17.27 g, 117mmol), and potassium phosphate (59.4 g, 280 mmol). The flask was purgedwith N₂ (5×) and then 1,4-dioxane (200 mL) and water (20 mL) were added.The resulting yellow suspension was bubbled with Ar for 15 min and then1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (Amphos,commercially available from Strem, 2.64 g, 3.73 mmol) was added, areflux condenser was attached and the reaction was warmed to 90° C. inan oil bath and stirred under N₂ for 16.5 h. The reaction was thencooled to RT. The reaction was diluted with water (250 mL), andextracted with EtOAc (2×250 mL). The organic layers were combined, dried(MgSO₄), and concentrated in vacuo. The residue was purified by flashchromatography on silica gel eluting with 0-20% EtOAc/hexanes) to afford(E)-5-methyl-2-(prop-1-en-1-yl)pyrimidine 29.01 (12.96 g, 97 mmol, 100%yield) as a yellow/orange oily solid. ¹H NMR (300 MHz, CDCl₃) δ 8.49 (s,2H), 7.01-7.20 (m, 1H), 6.57 (dd, J=15.6, 1.7 Hz, 1H), 2.29 (s, 3H),1.97 (dd, J=6.8, 1.6 Hz, 3H). LCMS-ESI (pos.) m/z: 135.2 (M+H)⁺.

(1R,2R)-1-(5-Methylpyrimidin-2-yl)propane-1,2-diol, Example 29.02

Racemic conditions. To a solution of(E)-5-methyl-2-(prop-1-en-1-yl)pyrimidine, 29.01 (5.75 g, 42.9 mmol) and4-methylmorpholine-4-oxide (7.53 g, 64.3 mmol) in acetone (60 mL) andwater (6 mL) was added osmium tetroxide, 4 wt. %, in water (0.681 mL,0.111 mmol). The resulting reaction mixture was stirred at RT under N₂for 21.5 h. LCMS showed complete conversion to a product correspondingto the mass of the desired product (M+H)⁺=169. The reaction was passedthrough a Varian Chem-Elut cartridge to remove water and concentrated invacuo. Water was still presen, and the residue was dissolved in DCM,dried (MgSO₄), and concentrated in vacuo. The residue was purified byflash chromatography (120 g SiO₂, 0-10% MeOH/DCM) to give the racemicsyn-diol (1S,2S)-1-(5-methylpyrimidin-2-yl)propane-1,2-diol and(2R,2R)-1-(5-methylpyrimidin-2-yl)propane-1,2-diol (5.85 g, 34.8 mmol,81% yield) as a light yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.59 (s,2H), 4.67 (br. s., 1H), 4.33 (br. s., 1H), 4.09-4.25 (m, 1H), 2.86 (d,J=7.2 Hz, 1H), 2.36 (s, 3H), 1.30 (d, J=6.6 Hz, 3H). LCMS-ESI (pos.)m/z: 169.2 (M+H). Chiral conditions. A batch of AD-mix-beta was preparedfrom: K₂OsO₂(OH)₄ (26 mg, 0.07 mmol); K₃Fe(CN)₆ (16.4 g, 49.9 mmol);K₂CO (6.89 g, 49.9 mmol)₃; and (DHQD)₂PHAL (125 mg, 0.16 mmol). In a 50mL round bottom flask was added t-BuOH (5 mL), water (5.00 mL), 1.4 g ofAD-mix-beta (prepared above) and methanesulfonamide (95 mg, 1.00 mmol).The mixture was stirred at RT until clear and then cooled to 0° C.(E)-5-Methyl-2-(prop-1-en-1-yl)pyrimidine (intermediate 29.01 168 mg, 1mmol) in t-BuOH (1 mL) was added, and the slurry was stirred at 0° C. 2h. LCMS (1.5 h) showed ˜10% conversion. The reaction was allowed to warmslowly to RT as the ice bath melted, and the mixture was stirred anadditional 22 h. LCMS showed ˜90% conversion. The reaction was quenchedwith saturated aqueous sodium sulfite (10 mL), and extracted with EtOAc(2×20 mL). The combined organic layers were washed with 2 N NaOH (10mL), dried (MgSO₄), and concentrated. The aqueous layer was extractedwith DCM (2×50 mL), EtOAc (2×50 mL), and 10% iPrOH in CHCl₃ (2×50 mL).The combined organic layers were concentrated, and the residue waspurified by flash column chromatography (12 g SiO₂, 5-100% 3:1EtOAc:EtOH/heptane) to give(1R,2R)-1-(5-methylpyrimidin-2-yl)propane-1,2-diol (Example 29.02, 88.6mg, 0.527 mmol, 52.7% yield) as a clear, colorless oil. Chiral Analysis:SFC Chiral Analysis showed the % ee to be 94.8% using an AS-H (100×2.1mm, 3 um), 10% organic modifier (IPA with 20 mM ammonia). 90% carbondioxide. F=1.0 mL/min, column temperature=RT, BRP=105 bar.

5-Methyl-2-((2R,3R)-3-methyloxiran-2-yl)pyrimidine, Example 29.03

To a solution of syn-diol(1R,2R)-1-(5-methylpyrimidin-2-yl)propane-1,2-diol 11.2 (1.46 g, 8.68mmol) in DCM (25 mL) (cooled with a RT water bath) was added1,1,1-trimethoxyethane (2.50 mL, 2.29 mmol). Chlorotrimethylsilane (2.50mL, 19.7 mmol) was then added in 2 portions 5 min apart. The reactionhad a small exotherm on the first portion of addition of TMSCl (23-28°C.). The reaction was stirred at RT under N₂ for 23 h. LCMS indicatedincomplete conversion. Thus, an additional 1.25 equiv. of1,1,1-trimethoxyethane (1.25 mL, 9.95 mmol) and chlorotrimethylsilane(1.25 mL, 9.85 mmol) were added, and the reaction was stirred for anadditional 24 h. LCMS; ((M+H)⁺=229). The reaction was then concentratedin vacuo. The residue was dissolved in MeOH (20 mL) and potassiumcarbonate (1.50 g, 10.85 mmol) was added and the reaction stirred at RTfor 4 h. LCMS (4 h) showed complete conversion to product correspondingto desired epoxide LCMS; ((M+H)⁺=151). The reaction was filtered, thefilter cake washed with DCM (5 mL), and the combined filtratesconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel eluting with 0-100% EtOAc/hexanes) toafford 5-methyl-2-((2R,3R)-3-methyloxiran-2-yl)pyrimidine 29.03 (1.00 g,6.6 mmol, 77%) as a clear, light yellow oil. ¹H NMR (300 MHz, CDCl₃) δ8.54 (s, 2H), 3.81 (d, J=1.9 Hz, 1H), 3.32-3.53 (m, 1H), 2.31 (s, 3H),1.50 (d, J=5.1 Hz, 3H). LCMS-ESI (pos.) m/z: 151.2 (M+H)⁺.

(1R,2S)-2-(Benzo[d]thiazol-2-ylthio)-1-(5-methylpyrimidin-2-yl)propan-1-ol,Example 29.04

To a solution of Example 29.03 (250 mg, 1.33 mmol) in DCM (5 mL) wasadded benzo[d]thiazole-2-thiol (245 mg, 1.465 mmol), followed bytris(((trifluoromethyl)sulfonyl)oxy)ytterbium (83 mg, 0.133 mmol). Thesuspension was heated in a 35° C. heating block for 17 h and showed 100%conversion to the desired product. The reaction was cooled to RT, loadedon a plug of silica, and purified by flash chromatography (12 g SiO₂,5-100% 3:1 EtOAc:EtOH/heptane) to afford(1R,2S)-2-(benzo[d]thiazol-2-ylthio)-1-(5-methylpyrimidin-2-yl)propan-1-ol29.04 (428 mg, 1.35 mmol, 100% yield) as a clear colorless oil. ¹H NMR(300 MHz, CDCl₃) δ 8.60 (s, 2H), 7.88 (d, J=7.6 Hz, 1H), 7.71-7.81 (m,1H), 7.42 (td, J=7.7, 1.3 Hz, 1H), 7.27-7.35 (m, 1H), 5.31 (s, 1H), 4.70(qd, J=7.1, 3.1 Hz, 1H), 2.32 (s, 3H), 1.33 (d, J=7.0 Hz, 3H). LCMS-ESI(pos.) m/z: 318.2 (M+H)⁺.

2-(((1R,2S)-1-Methoxy-1-(5-methylpyrimidin-2-yl)propan-2-yl)thio)benzo[d]thiazole,Example 29.05

To a 50 mL flask equipped with a magnetic stirrer was charged Example29.04 (350 mg, 1.103 mmol) in 2-methyltetrahydrofuran (1.1 mL). Thereaction mixture was cooled to −78° C. and potassiumbis(trimethylsilyl)amide (1.0 M solution in THF, 1.32 μL, 1.32 mmol))was added dropwise (total addition time: 2 min., turned to yellowsolution). The resulting mixture was stirred for 1 h and then methyltrifluoromethanesulfonate (374 μL, 3.31 mmol) was added dropwise (turnedto a lighter yellow solution). The reaction mixture was stirred at ˜78°C. for 15 min. LCMS showed complete conversion to the product. Thereaction mixture was quenched with a saturated aqueous NH₄Cl solution(30 mL) at −78° C. The reaction was allowed to warm to RT and theaqueous layer was back extracted with EtOAc (3×75 mL). The combinedorganic layers were washed with brine, dried (Na₂SO₄), and concentratedin vacuo. The material thus obtained was purified by chromatographythrough a Biotage 50 g ultra silica gel column, eluting with a gradientof 0-25% EtOAc in hexanes, to provide2-(((1R,2S))-1-methoxy-1-(5-methylpyrimidin-2-yl)propan-2-yl)thio)benzo[d]thiazole29.05 (0.32 g, 75% for two runs) as a light-yellow oil.

2-(((1R,2S)-1-Methoxy-1-(5-methylpyrimidin-2-yl)propan-2-yl)sulfonyl)benzo[d]thiazole,Example, Example 29.06

A solution of2-(((1R,2S)-1-methoxy-1-(5-methylpyrimidin-2-yl)propan-2-yl)thio)benzo[d]thiazole29.05 (313 mg, 0.94 mmol) in DCM (2.8 mL) at 0° C. was treated with3-chloroperoxybenzoic acid, 77% max. (476 mg, 2.13 mmol). The reactionwas stirred at 0° C. for 1 h before the ice bath was removed. LCMSshowed desired product, sulfoxide, and the presumed sulfoxide/sulfone.The mixture was allowed to warm to ambient temperature and stirred foran additional 40 h. The reaction was quenched with saturated aqueoussodium bisulfite (6 mL), saturated aqueous sodium bicarbonate (5 mL),and was then stirred for 10 min. The reaction was extracted with EtOAc(2×20 mL) and the organic layers were combined, washed with saturatedaqueous NaHCO₃ (10 mL), brine (10 mL), dried (MgSO₄) and filtered.Iodide/starch strip indicator showed no peroxide was present. Thefiltrates were concentrated to give a clear, colorless oil (360 mg).Purification of the residue by flash chromatography (40 g SiO₂, 0-100%3:1 EtOAc:EtOH/heptane) gave2-(((1R,2S)-1-methoxy-1-(5-methylpyrimidin-2-yl)propan-2-yl)sulfonyl)benzo[d]thiazole11.6 (285 mg, 0.78 mmol, 83% yield, 77% purity) as a white foam. ¹H NMR(300 MHz, CDCl₃) δ 8.57 (s, 2H), 8.18-8.28 (m, 1H) 7.97-8.05 (m, 1H),7.54-7.67 (m, 2H), 5.25-5.34 (m, 1H), 4.23 (qd, J=7.2, 3.1 Hz, 1H), 3.41(s, 3H), 2.31 (s, 3H), 1.49 (d, J=7.2 Hz, 3H). LCMS-ESI (pos.) m/z:364.0 (M+H).

Potassium(1R,2S)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfinate, Example29.07

To a solution of2-(((1R,2S)-1-methoxy-1-(5-methylpyrimidin-2-yl)propan-2-yl)sulfonyl)benzo[d]thiazole29.06 (268 mg, 0.74 mmol) in MeOH (1843 μL) was added potassiumcarbonate (204 mg, 1.48 mmol). The reaction was stirred at RT for 17 h.LCMS showed desired product formation as the sulfinic acid. LCMS-ESI(pos.) m/z: (M+H)⁺=231.1). The reaction was concentrated in vacuo(yellow solid) and used directly in the following step. Note: Someepimerization occurred in this reaction (˜15%)

(1R,2S)-1-Methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide,Example 29.0

To a suspension of potassium(1R,2S)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfinate (Example29.07, 198 mg, 0.74 mmol) in water (3.7 mL) was added potassium acetate(72.4 mg, 0.74 mmol), followed by hydroxylamine-o-sulfonic acid, 97%(167 mg, 1.476 mmol). The reaction mixture was stirred at RT for 4.5 h.LCMS showed desired product formation plus a small peak thatcorresponded to the stereoisomer. The reaction mixture was extractedwith EtOAc (2×) and the organic layers were combined, dried (Na₂SO₄),and concentrated in vacuo. The residue was loaded onto a silica gelcolumn eluting with 0-30% (3:1 EtOAc:EtOH)/DCM to afford(1R,2S)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide 29.0(114 mg, 0.465 mmol, 63% yield) as a white solid (contained ˜15% otherdiastereomer). ¹H NMR (300 MHz, CDCl₃) δ 8.63 (s, 2H), 5.10 (d, J=3.3Hz, 1H), 4.78 (br. s., 2H), 3.74 (qd, J=7.1, 3.3 Hz, 1H), 3.51 (s, 3H),2.36 (s, 3H), 1.33 (d, J=7.1 Hz, 3H). LCMS-ESI (pos.) m/z: 246.1 (M+H)⁺.

The compounds set forth in the following table were synthesizedfollowing the procedure in Example 29.0 using the known startingmaterial as described.

TABLE 6 Example Reagents Structure, Name and Data 29.1 2-bromo-5-methylpyrazine (commercially available from NOWA pharmaceuticals).

(1R,2S)-1-methoxy-1-(5-methylpyrazin- 2-yl)propane-2-sulfonamide.LCMS-ESI (pos.) m/z: 246.2 (M + H)⁺. 29.2 2-chloro-5- fluoropyrimidine(commercially available from Oakwood).

(1R,2S)-1-(5-fluoropyrimidin-2-yl)- 1-methoxypropane-2-sulfonamide.LCMS-ESI (pos.) m/z: 250.1 (M + H)⁺. 29.3 2,5- dichloropyrimidine(commercially available from Oakwood).

(1R,2S)-1-(5-chloropyrimidin-2-yl)- 1-methoxypropane-2-sulfonamide.LCMS-ESI (pos.) m/z: 265.9 (M + H)⁺. 29.4 2-chloropyrimidine(commercially available from Acros Organics).

(1R,2S)-1-methoxy-1-(pyrimidin- 2-yl)propane-2-sulfonamide. LCMS-ESI(pos.) m/z: 232.0 (M + H)⁺. 29.5 2-chloro-5- fluoropyrimidine(commercially available from Oakwood). EtOTf used in place of MeOTf in

Example 29.5. (1R,2S)-1-ethoxy-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide. LCMS-ESI (pos.) m/z: 264.0 (M + H)⁺. 29.62-chloro-5- fluoropyrimidine (commercially available from Oakwood).TBSOTf used in place of MeOTf in

Example 29.5. (1R,2S)-1-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyrimidin-2- yl)propane-2-sulfonamide. LCMS-ESI (pos.) m/z:350.1 (M + H)⁺. 29.7 2,5- dichloropyrimidine (commercially availablefrom Oakwood), EtOTf used in place of MeOTf in Example

29.05. (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-ethoxypropane-2-sulfonamide. LCMS-ESI (pos.) m/z: 279.9.

Example 29.8. Preparation of Example(1R,2S)-1-methoxy-1-(5-methoxypyrimidin-2-yl) propane-2-sulfonamide

(1R,2S)-1-Methoxy-1-(5-methoxypyrimidin-2-yl)propane-2-sulfonamide,Example 29.8

The title compound was obtained as a by-product of the synthesis of(1R,2S)-1-methoxy-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide(Example 29.2) during step 29.07 and isolated in the final step of thesynthesis of Example 29.2 to give the title compound 29.8 (240 mg, 10.2%yield) as a white solid. ¹H NMR (CDCl₃) δ 8.46 (s, 2H), 5.11 (d, J=3.4Hz, 1H), 4.77 (br. s, 2H), 3.97 (s, 3H), 3.67-3.77 (m, 1H), 3.50 (s,3H), 1.35 (d, J=7.0 Hz, 3H). LCMS-ESI (pos.) m/z: 284.1 (M+Na)⁺.

Example 30.0. Preparation of N,N-bis(4-methoxybenzyl)ethanesulfonamide

Bis(4-methoxybenzyl)amine, Example 30.1

4-Methoxybenzylamine (neat, 600 g, 4.37 mol, 1 eq) and4-methoxybenzaldehyde (532 mL, 4.37 mol, 1 eq) were added to a 10 Lround bottom flask at ambient temperature with stirring. The reactionspontaneously warmed and a white precipitate was observed. The mixturewas stirred for 1 h. To the above mixture was added anhydrous EtOH (4.8L) and stirring was continued at RT for 15-30 min. This was followed bythe addition of sodium borohydride granules (99 g, 2.62 mol, 0.6 eq)portionwise over ˜2 h (Note: During the addition of NaBH₄, the internaltemperature of the reaction rose to 42° C.), and the mixture was furtherstirred at ambient temperature overnight. The reaction was quenchedslowly with water (600 mL). The mixture was then concentrated on arotary evaporator at 50° C. The residue was partitioned between water (4L) and DCM (4 L). The aqueous layer was extracted with more DCM (2×2 L).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to give bis(4-methoxybenzyl)amine 30.1 (1112 g,99% yield) as a semi-solid. The material was used directly in the nextstep without further purification. ¹H-NMR (400 MHz, CDCl₃) δ 7.28 (t,J=7.12 Hz, 4H), 6.89 (d, J=8.60 Hz, 4H), 3.83 (app s, 6H), 3.76 (s, 4H)(—NH proton not observed). LCMS-ESI (pos.) m/z: =258.4 (M+H)⁺.

N,N-Bis(4-methoxybenzyl)ethanesulfonamide, Example 30.0

To a solution of bis(4-methoxybenzyl)amine 30.1 (900 g, 3.49 mol, 1 eq)in DCM (9 L) was added TEA (634 mL, 4.55 mol, 1.3 eq) followed bydropwise addition of ethanesulfonyl chloride (399 mL, 4.19 mol, 1.2 eq).(The internal temperature was kept between 5-10° C. during the additionof the ethanesulfonyl chloride). Once the addition was complete, thecooling bath was removed. After 1.5 h, TLC showed complete loss ofstarting material. The reaction was quenched by the addition of water (4L) to the reaction mixture. The layers were separated and the aqueouslayer extracted with DCM (2×2 L). The combined organic layers werewashed with brine (2×1 L), dried over Na₂SO₄, and concentrated in vacuo.The material thus obtained was adsorbed onto a plug of silica gel andpurified by chromatography (silica gel (60-120 mesh) eluting with agradient of 10-80% EtOAc in hexanes) to provide the title compound 30.0(1125 g, 3.22 mol, 92%) as white solid. ¹H-NMR (400 MHz, CDCl₃) δ 7.23(dd, J=2.08, 6.62 Hz, 4H), 6.90 (dd, J=2.12, 6.60 Hz, 4H), 4.29 (s, 4H),3.83 (app s, 6H), 2.92 (q, J=7.40 Hz, 2H), 1.33 (t, J=7.40 Hz, 3H).GC-MS (ESI pos. ion) m/z: =372.2 (M+Na)⁺.

Example 31.0: Preparation of(1S,2S)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide

5-Methylpyrimidine-2-carbonitrile, Example 31.1

A solution of 2-chloro-5-methylpyrimidine (500 g, 3889 mmol, 1.0 equiv)in DMF (5000 mL) was degassed with N₂ for 20 min and dppf (108 g, 194mmol, 0.05 equiv) and Pd₂(dba)₃ (178 g, 194 mmol, 0.05 equiv) were addedto the reaction mixture. Zn(CN)₂ (685 g, 5834 mmol, 1.5 equiv) wasadded, and the reaction mixture was heated at 100° C. for 16h. Thereaction was quenched with water (5 L) and stirred for 10 min. Thereaction mixture was then filtered through a pad of Celite® brand filteraid. Filtrate was diluted with water (4 L) and extracted with EtOAc (2×4L). The combined organic layers were washed with brine (4 L), dried overNa₂SO₄, filtered and concentrated in vacuo to give the initial productwhich was further purified by column chromatography using silica gel(60-120 mesh) and 0-10% EtOAc in hexanes to obtain Example 31.1 (330 g,71%) as and off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.89 (s, 2H),2.39 (s, 3H).

(R)—N,N-Bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)-1-oxopropane-2-sulfonamideand(S)—N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)-1-oxopropane-2-sulfonamide,Example 31.2

A solution of Example 30.0 (293 g, 839 mmol, 2.0 equiv) in THF (2 L) wasadded isopropylmagnesium chloride (420 mL, 839 mmol, 2.0 equiv, 2.0 M indiethyl ether) at 0° C. The reaction mixture was stirred at RT for 3 h.To the reaction mixture was added 5-methylpyrimidine-2-carbonitrile (50g, 420 mmol, 1.0 equiv) in THF (100 mL) at 0° C., and the mixture wasstirred at RT for 2h. The reaction was then quenched with 1.5 N HCl (500mL) and water (2 L) and stirred for 10 min. The mixture was extractedwith EtOAc (2×1 L), and the combined organic layers were washed withbrine (500 mL), dried over Na₂SO₄ and filtered. The organic layer wasconcentrated in vacuo to give the initial compound which was purified bycolumn chromatography using silica gel (100-200 mesh) and 0-50% EtOAc inhexanes as eluent to obtain Example 31.2 (60 g, 30% yield) as a brownliquid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (s, 2H), 7.15-7.09 (m, 4H),6.85-6.80 (m, 4H), 4.34-4.18 (m, 5H), 3.71 (app s, 6H), 2.39 (s, 3H),1.50 (d, J=6.9 Hz, 3H). LCMS-ESI (pos.) m/z: (M+H)⁺: 470.0.

(E)-1-Isopropoxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)prop-1-ene-2-sulfonamide,Example 31.3

A solution of Example 31.2 (120 g, 256 mmol, 1.0 equiv) in DMF (1.2 L)was added 2-iodopropane (129 mL, 1278 mmol, 5.0 equiv) and potassiumcarbonate (70.6 g, 511 mmol, 2.0 equiv). The reaction mixture wasstirred at 60° C. for 14 h. The reaction was then quenched with water (1L), stirred for 10 min and extracted with EtOAc (2×1 L). The combinedorganic layers were washed with brine (1 L), dried over Na₂SO₄, filteredand concentrated in vacuo to give the initial material. The initialproduct was purified by column chromatography using silica gel (100-200mesh) and 0-50% EtOAc in hexanes as eluent to obtain Example 31.3 (75 g,57.4% yield) as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.72 (s,2H), 7.09 (d, J=8.3 Hz, 4H), 6.86 (d, J=8.3 Hz, 4H), 4.16 (s, 4H), 3.73(s, 3H), 3.73 (s, 3H), 3.71-3.67 (m, 1H), 2.31 (s, 3H), 1.87 (s, 3H),1.19-1.16 (m, 6H). LCMS-ESI (pos.) m/z: (M+H)⁺: 512.1.

(1S,2R)-1-Isopropoxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide,Example 31.4

To a solution of Example 31.3 (180 g, 352 mmol, 1.0 equiv) in MeOH (1.8L) was added zinc triflate (256 g, 704 mmol, 2.0 equiv) and(S)—RuCl[(p-cymene(BINAP)]Cl (6.54 g, 7.04 mmol, 0.02 equiv) were added,and the mixture was heated at 60° C. under H₂ pressure (60 psi) for 16h.The reaction mixture was concentrated in vacuo to obtain the initialproduct which was further purified by column chromatography using silicagel (60-120 mesh) and 0-50% EtOAc in DCM as eluent to obtain Example31.4 (140 g, 77%, 92% ee) as an off white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.71 (s, 2H), 7.25-7.15 (m, 4H), 6.95-6.75 (m, 4H), 4.82 (dd,J=7.8, 1.8 Hz, 1H), 4.39 (d, J=15.6 Hz, 2H), 4.13 (d, J=15.7 Hz, 2H),3.82 (qd, J=8.5, 7.9, 6.0 Hz, 1H), 3.65 (m, 6H), 3.41-3.35 (m, 1H), 2.27(s, 3H), 1.12 (dd, J=6.2, 1.8 Hz, 3H), 1.02 (dd, J=7.1, 2.0 Hz, 3H),0.96 (dd, J=6.3, 1.8 Hz, 3H). LCMS-ESI (pos.) m/z: (M+H)⁺: 514.2.

(1 S,2S)-1-Isopropoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide,Example 31.0, Example 31.0

To a solution of Example 31.4 (140.0 g, 273 mmol, 1.0 equiv) in DCM (500mL) was added TFA (250 mL) at 0° C., and the reaction mixture wasallowed to stir at RT for 16 h. The reaction mixture was concentrated invacuo to obtain the initial material which was dissolved in DCM (1 L)and washed with a saturated aqueous NaHCO₃ solution (1 L). The organiclayer was dried over Na₂SO₄, filtered and concentrated in vacuo toobtain the initial material which was further purified by columnchromatography using silica gel (60-120 mesh) and 0-2% MeOH in DCM toobtain Example 31.0 (72 g, 97% yield, 90% ee) as an off white solid.Example 31.0 (72 g, 90% ee) was suspended in IPA (500 mL) and heated to70° C. until the mixture became homogeneous. Once the solution becamehomogeneous, the mixture was cooled to RT overnight. The white solidthus obtained was filtered and dried under vacuum to obtain compound-6(30 g, >99% ee). The mother liquor was concentrated and the solidobtained was recrystallized again following the same procedure. ¹H NMR(400 MHz, DMSO-d₆) δ 8.70 (d, J=2.3 Hz, 2H), 6.45 (d, J=2.4 Hz, 2H),4.68 (dd, J=8.8, 2.5 Hz, 1H), 3.59-3.52 (m, 1H), 3.48 (ddd, J=9.7, 7.4,4.9 Hz, 1H), 2.29 (d, J=2.6 Hz, 3H), 1.13 (dd, J=6.1, 2.5 Hz, 3H), 0.93(dd, J=7.1, 2.5 Hz, 3H), 0.88 (dd, J=6.3, 2.5 Hz, 3H). LCMS-ESI (pos.)m/z: (M+H)⁺: 274.1.

The compounds in the following table were synthesized following theprocedure in Example 31.0 using the known starting material asdescribed.

TABLE 7 Example Reagents Structure, Name and Data 31.012-chloro-5-chloro- pyrimidine.

(1S,2S)-1-(5-chloropyrimidin-2-yl)- 1-isopropoxypropane-2-sulfonamide.LCMS ESI (pos.) m/z: 234.2 (M + H)⁺. 31.02 2-chloro-5- methylpyrazine.

(1S,2S)-1-isopropoxy-1-(5-methylpyrazin- 2-yl)propane-2-sulfonamide.LCMS ESI (pos.) m/z: 274.1 (M + H)⁺.

Example 32.0. Preparation of(2S,3R)-3-(5-chloropyridin-2-yl)butane-2-sulfonamide

(2S,3R)-3-(5-Chloropyridin-2-yl)butane-2-sulfonamide, Example 32.0

To a solution of (E)-2-(5-chloropyridin-2-yl)ethenesulfonamide (10 g,40.5 mmol) in MeOH (100 mL) was added zinc trifluoromethanesulfonate(2.95 g, 8.11 mmol), bis(1,5-cyclooctadiene)rhodium(I) tetrafluroborate(0.329 g, 0.811 mmol) and(S)-1-[(R)-2-(di-1-naphthylphosphino)ferrocenyl]-ethyl-di-tert-butylphosphine(0.651 g, 1.013 mmol). The reaction mixture was degassed with argon andhydrogen three times and charged with hydrogen (50 Psi) in 200 mL. Thereaction was mini-claved at RT for 16 h followed by heating at 65° C.for 16 h checked by TLC for completion of reaction. The reaction masswas concentrated in vacuo to give the initial product which was purifiedby column chromatography (silica gel 60-120 mesh) using 40-45% of EtOAcin petroleum ether as an eluent to obtain the desired product Example32.0 (9 g, 36.2 mmol, 89%) as a brownish solid in 82% ee.Recrystallization from i-PrOH yielded >97% ee material. 1H NMR (400 MHz,DMSO-d₆) δ 1.19 (d, J=7.05 Hz, 3H) 1.29 (d, J=7.05 Hz, 3H) 3.46 (qd,J=7.08, 3.84 Hz, 1H) 3.63 (qd, J=7.08, 3.84 Hz, 1H) 6.82 (s, 2H) 7.36(d, J=8.50 Hz, 1H) 7.88 (dd, J=8.50, 2.70 Hz, 1H) 8.56 (d, J=2.28 Hz,1H). LCMS-ESI (pos.) m/z: 249.0 (M+H)⁺.

Example 33.0. Preparation of(1R,2R)-1-isopropoxy-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide or(1S,2S)-1-isopropoxy-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide

5-Methylpyrazine-2-carbaldehyde, Example 33.1

A solution of LAH (164.0 mL, 0.164 mol, 1.0 M in THF, 0.5 equiv.) wasadded to a suspension of methyl 5-methylpyrazine-2-carboxylate (50 g,0.328 mol, 1.0 equiv.) in anhydrous THF (750 mL) at −78° C. The internaltemperature was kept below −72° C. during the addition of LAH. Oncompletion of addition, the reaction mixture was left, to stir at −78°C. for a further 20 min and then quenched with glacial AcOH (50.0 mL) atthe same temperature. The resulting mixture was warmed to RT and thevolatiles were removed by evaporation under pressure. The residue wasdissolved in hydrochloric acid (1.5N, 500 mL) and extracted with DCM(2×2 L). The extracts were combined, washed with a saturated aqueoussodium hydrogen carbonate solution (2×500 mL), (Note: no product wasobserved in the HCl or aqueous sodium hydrogen carbonate solution) driedover anhydrous Na₂SO₄, and concentrated in vacuo to yield a brown oil.The initial product was purified by column chromatography (silica gel60-120 mesh) eluting with a gradient of 10% EtOAc in petroleum ether toprovide the title compound as a pale yellow liquid (21.3 g, 53%). TLCInfo: (9.0/1.0 petroleum ether/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ 10.14(s, 1H), 9.07 (d, J=1.5 Hz, 1H), 8.63 (d, J=1.4 Hz, 1H), and 2.70 (s,3H). LCMS-ESI (pos.) m/z: 123 (M+H)⁺.

(1R,2S)-1-Hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrazin-2-yl)propane-2-sulfonamideand(1S,2R)-1-hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide,Example 33.2

To a solution of N,N-bis(4-methoxybenzyl)ethanesulfonamide (Example12.0, 73.13 g, 0.209 mol, 1.2 equiv.) in anhydrous THF (600 mL) at −78°C. was added n-butyl lithium (83.71 mL, 0.209 mol, 2.5 M solution inhexanes, 1.2 equiv.) via additional funnel slowly, and the resultingmixture was stirred for 10 min. Then a solution of5-methylpyrazine-2-carbaldehyde (Example 33.1, 21.3 g, 0.174 mol, 1.0equiv.) in anhydrous THF (150 mL) was added, and the resulting mixturewas stirred at the same temperature for 45 min and then allowed to warmto RT for 2 h. The reaction mixture was quenched by the addition ofaqueous ammonium chloride (200 mL) and extracted with EtOAc (2×2 L). Thecombined organic layers were washed with brine (2×500 mL) (Note: noproduct was observed in the ammonium chloride or brine layer). Afterdrying over anhydrous Na₂SO₄, the filtrate was concentrated in vacuo, toafford an oil. The oil was purified by flash column chromatography(silica gel, 230-400 mesh) to afford the two isomers. The faster movingisomer (32 g as a white solid) was obtained from the column with agradient of 10% to 30% EtOAc in petroleum ether. ¹H NMR (400 MHz,DMSO-d₆) δ 8.61 (d, J=1.5 Hz, 1H), 8.51 (d, J=1.5 Hz, 1H), 7.22-7.11 (m,4H), 6.90-6.80 (m, 4H), 6.10 (d, J=5.9 Hz, 1H), 5.29 (dd, J=5.9, 2.2 Hz,1H), 4.36-4.16 (m, 4H), 3.73 (m, 6H), 3.70-3.66 (m, 1H) 2.50 (mergedwith solvent peak, 3H) and 1.10 (d, J=7.0 Hz, 3H). LCMS-ESI (pos.) m/z:472.4 (M+H)⁺.

(1S,2S)-1-Hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methyl-pyrazin-2-yl)propane-2-sulfonamideand(1R,2R)-1-hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methyl-pyrazin-2-yl)propane-2-sulfonamide,Example 28.3

Further elution of the mixture with a gradient of 30% to 35% EtOAc inpetroleum ether yielded Example 33.3 (16 g, pale yellow gummy liquid).¹H NMR (400 MHz, CDCl₃) δ 8.62 (d, J=1.6 Hz, 1H), 8.44 (d, J=1.5 Hz,1H), 7.25-7.12 (m, 4H), 6.93-6.82 (m, 4H), 5.17 (d, J=7.1 Hz, 1H), 4.47(d, J=15.2 Hz, 3H), 4.14 (d, J=15.4 Hz, 2H), 3.82 (d, J=1.8 Hz, 6H),3.66-3.61 (m, 1H), 2.60 (d, J=2.0 Hz, 3H), and 1.08 (dd, J=7.2, 2.1 Hz,3H). LCMS-ESI (pos.) m/z: 472.4 (M+H)⁺.

(1S,2S)-1-Isopropoxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrazin-2-yl)propane-2-sulfonamideand(1R,2R)-1-isopropoxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide,Example 33.4

To a flask containing(1S,2S)-1-hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrazin-2-yl)propane-2-sulfonamideand(1R,2R)-1-hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide(Example 33.3, 4.16 g, 8.81 mmol) and isopropyl iodide (12.3 mL, 123mmol) in anhydrous toluene (35 mL) was added silver(I) oxide (4.17 g,18.0 mmol) carefully in portions. Upon complete addition of silveroxide, the reaction was protected from light and heated to an internaltemperature of 72° C. After 60 h, the mixture was cooled to RT and thenfiltered through a Chemglass disposable filter that was rinsed withEtOAc. The filtrate was concentrated in vacuo. The dark brown residuewas loaded onto a silica gel column (10-55% EtOAc in heptanes).Fractions containing the product were combined and then concentrated invacuo to afford (1S,2S)-1-isopropoxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrazin-2-yl)propane-2-sulfonamideand(1R,2R)-1-isopropoxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide(Example 33.4, 1.52 g, 2.97 mmol, 34% yield) as a dark brown oil thatwas used without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 8.58(d, J=1.5 Hz, 1H), 8.54 (d, J=0.8 Hz, 1H), 7.20-7.15 (m, 4H), 6.89-6.85(m, 4H), 4.81 (d, J=7.0 Hz, 1H), 4.35-4.29 (m, 2H), 4.20-4.13 (m, 2H),3.76-3.71 (m, 7H), 3.39 (quin, J=6.1 Hz, 1H), 2.51 (s, 3H), 1.13 (d,J=6.0 Hz, 3H), 1.05 (d, J=7.3 Hz, 3H), 0.99 (d, J=6.2 Hz, 3H). LCMS-ESI(pos.), m/z: 514.0 (M+H)⁺.

(1R,2R)-1-Isopropoxy-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide and(1S,2S)-1-isopropoxy-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide,Example 33.5

Anisole (1.3 mL, 11.9 mmol) was added to a flask containing Example 33.4(1.5 g, 3 mmol) and DCM (7.5 mL). The homogeneous solution was cooled inan ice-water bath. After 15 mins, TFA (7.6 mL, 99 mmol) was addeddropwise to the reaction solution. Upon complete addition of TFA, thereaction was allowed to warm to RT. After 20 h, the brownish reactionsolution was concentrated in vacuo. The residue was loaded onto a silicagel column (15-85% EtOAc in heptanes). Fractions containing the productwere concentrated in vacuo to afford Example 33.5 (714 mg, 2.6 mmol, 88%yield) as an off white solid. LCMS-ESI (pos.), m/z: 274.0 (M+H)⁺.

(1R,2R)-1-Isopropoxy-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide or(1S,2S)-1-isopropoxy-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide,Example 33.6

Example 33.5 (714 mg, 2.6 mmol) was purified by preparative SFC usingthe following method: Column: IC (2×25 cm) Mobile Phase: 70:30 (A:B) A:Liquid CO₂, B: iPrOH to afford peak 1 as Example 33.6 (293 mg, 1.07mmol, 36% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (d, J=1.5 Hz, 1H),8.53 (d, J=0.8 Hz, 1H), 6.52 (s, 2H), 4.77 (d, J=7.0 Hz, 1H), 3.56-3.45(m, 2H), 1.15 (d, J=6.0 Hz, 3H), 1.05 (d, J=7.0 Hz, 3H), 0.96 (d, J=6.2Hz, 3H). (Obscured CH₃ in DMSO peak). LCMS-ESI (pos.), m/z: 274.2(M+H)⁺.

(1R,2R)-1-Isopropoxy-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide or(1S,2S)-1-isopropoxy-1-(5-methylpyrazin-2-yl)propane-2-sulfonamideExample 33.0

Further elution under the conditions described in Example 33.5 deliveredthe second eluting peak as Example 33.0 (303 mg, 1.11 mmol, 37% yield).¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (d, J=1.5 Hz, 1H), 8.53 (d, J=1.0 Hz,1H), 6.52 (s, 2H), 4.77 (d, J=7.0 Hz, 1H), 3.58-3.44 (m, 2H), 1.27-1.14(m, 3H), 1.05 (d, J=7.0 Hz, 3H), 1.00-0.91 (m, 3H). (Obscured CH₃ inDMSO peak). LCMS-ESI (pos.), m/z: 274.2 (M+H)⁺.

Example 34.0. Preparation of(1R,2S)-1-((tert-butyldimethylsilyl)oxy)-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide

5-Methyl-2-vinylpyrimidine, Example 34.1

A 3 L 3-necked round bottom flask was fitted with a reflux condenser, atemperature controller and a septum and was charged with2-chloro-5-methylpyrimidine (81 mL, 778 mmol), potassiumvinyltrifluoroborate (156 g, 1167 mmol), triphenylphosphine (18.02 mL,78 mmol), cesium carbonate (156 mL, 1945 mmol) and a large stir bar.Water (1565 mL) was added and the mixture was stirred for several minand then THF (244 mL) was added. Argon was bubbled through the mixturefor 5 min and then palladium (II) chloride (1.72 g, 38.9 mmol) wasadded. The reaction was further sparged with argon for 5 mins. Thetemperature was raised to 62° C. and stirring was continued tocompletion. The reaction was then cooled to RT and filtered through twoWhatman GF/F filter cups, rinsing with ether. The mixture wastransferred to a separatory funnel, and the layers were separated. Theaqueous layer was further extracted with diethyl ether (4×200 mL). Theorganic layers were combined and dried over anhydrous MgSO₄ and thenfiltered. The mixture was partially concentrated on the rotaryevaporator at 20° C. and 115 torr for an extended period of time to givean orange liquid. The material was further purified by Kugelrohrdistillation to isolate the title compound (65.4 g, 70%) as a lightyellow oil. ¹H NMR (400 MHz, CDCl₃) δ 2.31 (s, 3H), 5.68 (d, J=10.56 Hz,1H), 6.55 (d, J=17.22 Hz, 1H), 6.86 (dd, J=17.41, 10.56 Hz, 1H), 8.54(s, 2H). LCMS-ESI (pos.) m/z: 121.1 (M+H)⁺.

1-(5-Methylpyrimidin-2-yl)ethane-1,2-diol, Example 34.2

To a 2 L round-bottom flask was added 5-methyl-2-vinylpyrimidine (64.5g, 537 mmol), osmium tetroxide (0.204 mL, 3.93 mmol), 1,4-dioxane (537mL, 537 mmol), 4-methylmorpholine-N-oxide, 50% wt. in water (40 mL, 341mmol) and 4-methylmorpholine-4-oxide (94 g, 805 mmol). The reactionmixture was stirred over 2 d. LCMS showed that the reaction was completeand the solvent was removed in vacuo. The compound was purified bysilica gel. The gradient was 100% heptanes for 3CV's, then 0-100%EtOAc-EtOH (3:1) in heptanes for 6 CV's, then 100% EtOAc:EtOH (3:1) for5 CV's. The desired compound was collected and concentrated in vacuo.The material was triturated with 40% EtOAc in hexanes to give a solid,which was filtered. The solid was washed with 20% EtOAc in hexanesseveral times and then dried to give the title compound (67.3 g). ¹H NMR(400 MHz, CDCl₃) δ 8.59 (s, 2H), 4.81-4.98 (m, 1H), 3.88-4.19 (m, 2H),2.36 (s, 3H).

5-Methylpyrimidine-2-carbaldehyde, Example 34.3

A 5 L flask equipped with a mechanical stirrer was charged with1-(5-methylpyrimidin-2-yl)ethane-1,2-diol (64.3 g, 417 mmol),1,4-dioxane (1043 mL) and water (261 mL). The reaction was cooled in anice-water bath. Sodium periodate (223 g, 1043 mmol) was added and theinternal temperature was monitored until it returned to RT. The reactionwas further stirred at RT for 2 hr and 20 min. DCM (2 L) was then added.The resulting solution was filtered through a plug of dried MgSO₄ (700g). The plug was washed with DCM (7 L). The solvent was concentrated invacuo and the aldehyde was azeotroped with toluene to deliver the titlecompound (44 g) as a white solid. LCMS-ESI (pos.) m/z: 122.8 (M+H)⁺.

(1R,2S)-1-Hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamideand(1S,2S)-1-hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamideand(1R,2R)-1-hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamideand(1S,2R)-1-hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamideExample 34.4

A 3 L flask was charged with N,N-bis(4-methoxybenzyl)ethanesulfonamide(Example 30.0, 151 g, 432 mmol) and anhydrous THF (1200 mL) undernitrogen and then equipped with a pre-dried addition funnel undernitrogen. The flask was cooled in a dry ice-acetone bath. n-Butyllithium(1.6 M, 270 mL, 432 mmol) was first cannulated into the additionalfunnel. It was added slowly into the reaction flask and stirred for 10min. 5-Methylpyrimidine-2-carbaldehyde (34.3, 44 g, 360 mmol) in THF(300 mL) was then cannulated into the reaction. The reaction continuedat −78° C. for 45 min and then was warmed to RT and stirred for 2 h and10 min. A saturated solution of ammonium chloride was then added toquench the reaction, and the mixture was extracted with EtOAc andconcentrated in vacuo to give the product.

(1R,2S)-1-Hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamideand(1S,2R)-1-hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide,Example 34.5

The mixture of diastereomers was separated and purified on silica geleluting with 0-50% EtOAc gradient in DCM to give the title compound(56.4 g). LCMS-ESI (pos.) m/z: 472.1 (M+H)⁺.

(1S,2S)-1-Hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamideand(1R,2R)-1-hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamideExample 34.6

Further elution under the conditions described in Example 34.5 deliveredthe title compound. LCMS-ESI (pos.) m/z: 472.1 (M+H)⁺.

(1R,2S)-2-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-1-(5-methylpyrimidin-2-yl)propyl4-nitrobenzoate, Example 34.7

To a stirred solution of Example 34.6 (22.7 g, 48.1 mmol) in toluene(241 mL) was added 4-nitrobenzoic acid (12.07 g, 72.2 mmol), andtriphenylphosphine (18.94 g, 72.2 mmol) followed by dropwise addition of(E)-diisopropyl diazene-1,2-dicarboxylate (14.22 mL, 72.2 mmol). Themixture was stirred at RT overnight and showed the desired product byLCMS. The reaction was concentrated in vacuo and purified on silica geleluting with 0-50% EtOAc/hexanes to give the desired compound(1R,2S)-2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-(5-methylpyrimidin-2-yl)propyl4-nitrobenzoate (29.9 g, 48.1 mmol, 100% yield). LCMS-ESI (pos.) m/z:621.3 (M+H)⁺.

(1R,2S)-2-(N,N-Bis(4-methoxybenzyl)sulfamoyl)-1-(5-methylpyrimidin-2-yl)propyl4-nitrobenzoate, Example 34.9

To a stirred solution of 34.7 (76 g, 122 mmol) in MeOH (612 mL) at 0° C.was added potassium carbonate (16.92 g, 122 mmol). The mixture wasallowed to warm to RT over 1 h and then showed the desired product byLCMS. The reaction was concentrated in vacuo and purified on silica geleluting with 0-40% EtOAc in hexanes to give(1R,2S)-1-hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide.LCMS-ESI (pos.) m/z: 4720 (M+H)⁺.

(1R,2S)-1-((tert-Butyldimethylsilyl)oxy)-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide,Example 34.0

To a stirred solution of(1R,2S)-1-hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide(34.9, 28 g, 59.4 mmol) in DCM (297 mL, 59.4 mmol) at 0° C. was addedtert-butyldimethylsilyl trifluoromethanesulfonate (15.00 mL, 65.3 mmol),followed by TEA (9.12 mL, 65.3 mmol). The mixture was allowed to warm toRT over 1 h and showed the desired product by LCMS. The reaction wasconcentrated in vacuo, and the product thus obtained was purified onsilica gel eluting with 0-30% EtOAc in hexanes to give the desiredcompound(1R,2S)-1-((tert-butyldimethylsilyl)oxy)-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide(15 g, 25.6 mmol, 43.1% yield). LCMS-ESI (pos.) m/z: 586.0 (M+H)⁺.

Example 35.0. Preparation of(2R,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methoxy-2-pyrazinyl)-2-butanesulfonamideand(2R,3S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methoxy-2-pyrazinyl)-2-butanesulfonamideand(2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methoxy-2-pyrazinyl)-2-butanesulfonamideand(2S,3S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methoxy-2-pyrazinyl)-2-butanesulfonamide

(2R,3R)-3-(5-methoxypyrazin-2-yl)butane-2-sulfonamide and(2R,3S)-3-(5-methoxypyrazin-2-yl)butane-2-sulfonamide and(2S,3R)-3-(5-methoxypyrazin-2-yl)butane-2-sulfonamide and(2S,3S)-3-(5-methoxypyrazin-2-yl)butane-2-sulfonamide, Example 35.0

Example 35.0 was synthesized following the procedure in Example 32.0using 2-bromo-5-methoxypyrazine (commercially available from Ark Pharm,Inc.). LCMS-ESI (pos.) m/z: 246.2 (M+H)⁺.

Example 36.0. Preparation of(2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-((2R)-1,4-dioxan-2-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methoxy-2-pyrimidinyl)-2-butanesulfonamideor(2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-((2R)-1,4-dioxan-2-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methoxy-2-pyrimidinyl)-2-butanesulfonamide

(2S,3R)-3-(5-Methoxypyrimidin-2-yl)butane-2-sulfonamide, Example 36.1

A round bottom flask was charged with(2S,3R)-3-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide (575 mg, 2.47mmol, Example 27.1), MeOH (7 mL), and potassium carbonate (679 mg, 4.91mmol). The reaction was stirred at RT. After 48 h, the reaction washeated to 50° C. and stirred for 24 h. The temperature was then aised to65° C. and the reaction was stirred for 48 h. LCMS-ESI showed thereaction was 75% complete. The reaction was allowed to cool to RT andfiltered. The solids were rinsed with MeOH (2×5 mL). The filtrate wasconcentrated in vacuo and adsorbed onto a plug of silica gel andchromatographed through a RediSep® pre-packed silica gel column, elutingwith 0-40% EtOAc:EtOH (3:1) in heptanes. The organic layers from severalfractions were concentrated in vacuo to give a mixture of startingmaterial and the title compound (56 mg, 0.23 mmol, 9% yield) as anoff-white solid. The fractions were washed with an aqueous saturatedsolution of NaCl and extracted with CHCl₃:IPA (9:1, 3×15 mL). Thecombined organic layers were dried over MgSO₄ and concentrated in vacuoto give more title compound (114 mg). The material was carried forwardas obtained. LCMS-ESI (pos.) m/z: 246.1 (M+H)⁺.

Example 37.0. Preparation of(3R,5S)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-((2R)-1,4-dioxan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-(1-methylethoxy)-3-piperidinesulfonamideor(3R,5S)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-((2S)-1,4-dioxan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-(1-methylethoxy)-3-piperidinesulfonamideor(3S,5R)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-((2R)-1,4-dioxan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-(1-methylethoxy)-3-piperidinesulfonamideor(3S,5R)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-((2S)-1,4-dioxan-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-(1-methylethoxy)-3-piperidinesulfonamide

5-Hydroxypyridine-3-sulfonamide, Example 37.1

To a 100 mL round-bottom flask was added 5-bromopyridine-3-sulfonamide(commercially available from Enamine, KIEV, Ukraine) (0.486 g, 2.05mmol),2-di-t-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-tri-i-isopropylbiphenyl(commercially available from Strem Chemicals, Inc., MA, USA) (0.079 g,0.16 mmol) and Pd₂(dba)₃ (Sigma-Aldrich Chemical Company, Inc.) (0.038g, 0.041 mmol). The flask was placed under vacuum and back-filled withpotassium hydroxide (0.345 g, 6.15 mmol) solution in dioxane (5 mL) andwater (5 mL). The reaction mixture was then stirred at 100° C. under N₂for 17 h. LCMS analysis indicated the reaction was complete. Thereaction mixture was allowed to cool to RT. The reaction mixture wasdiluted with 1 N HCl and washed with Et₂O. The aqueous phase wasconcentrated in vacuo to afford the title compound 37.1 (0.387 g, 2.22mmol, 100% yield) as a white solid, which was directly used in the nextstep without further purification. LCMS-ESI (pos.), m/z: 175.1 (M+H)⁺.

5-Isopropoxypyridine-3-sulfonamide, Example 37.2

To a suspension of 5-hydroxypyridine-3-sulfonamide, Example 37.1 (1.1 g,6.32 mmol) in THF (16 mL) and IPA (16 mL) was added triphenylphosphine(1.99 g, 7.58 mmol). The mixture was bubbled with argon for 3 min beforediisopropyl azodicarboxylate (1.49 mL, 7.58 mmol) was added dropwise at0° C. under N₂ stream. The reaction was then stirred at 0° C. to RT for15 h. The reaction mixture was concentrated in vacuo. The material wasabsorbed onto a plug of silica gel and purified by chromatographythrough a RediSep-Sep pre-packed silica gel column (40 g), eluting witha gradient of 0% to 100% EtOAc in heptane, to provide the enrichedproduct fractions which were combined and extracted with 1N HCl. Thedesired product was enriched in acidic aqueous solution which was thenmodified by a saturated aqueous NaHCO₃ to pH>8. The basic aqueoussolution was then extracted with DCM. The organic extract was washedwith brine and dried over Na₂SO₄. The solution was filtered andconcentrated in vacuo to give Example 37.2,5-isopropoxypyridine-3-sulfonamide (0.95 g, 70% yield) as a white solid.LCMS-ESI (pos.), m/z: 217.2 (M+H)⁺.

(3S,5R)-5-Isopropoxypiperidine-3-sulfonamide and(3R,5R)-5-isopropoxypiperidine-3-sulfonamide and(3S,5S)-5-isopropoxypiperidine-3-sulfonamide and(3R,5S)-5-isopropoxypiperidine-3-sulfonamide, Example 37.3

A solution of Example 37.2 (1.8 g, 8.32 mmol) in AcOH (41.6 mL) wasbubbled with argon gas for 2 min before platinum (IV) oxide (1.89 g,8.32 mmol) was added under argon stream. The above reaction mixture wasthen stirred at RT under 45 psi of hydrogen gas for two d. Celite® brandfilter aid (5 g) was then added to the reaction mixture. The mixture wasstirred at RT for 10 min. The mixture was then filtered and the solutionwas concentrated in vacuo to give the initial product mixture as a lightyellow oil, which was used as such in the next step. LCMS-ESI (pos.),m/z: 223.3 (M+H)⁺.

(3R,5R)-1-(5-Fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3-sulfonamideand(3S,5R)-1-(5-fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3-sulfonamideand(3S,5S)-1-(5-fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3-sulfonamideand(3R,5S)-1-(5-fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3-sulfonamide,Example 37.4

To a 40 mL vial (with pressure release septa) was added Example 37.3(2.0 g, 4.96 mmol) and 2-chloro-5-fluoropyrimidine (3.29 g, 24.79 mmol).The reaction mixture was stirred at 90° C. for 21 h. LCMS indicated thereaction was complete. The reaction mixture was then concentrated invacuo. The initial material was absorbed onto a plug of silica gel andpurified by chromatography through RediSep-Sep pre-packed silica gelcolumn (40 g), eluting with a gradient of 0% to 100% EOAc in heptane, toprovide Example 37.4 as a mixture of diastereomers (0.5 g, 1.6 mmol, 32%yield) and as an off-white solid. LCMS-ESI (pos.), m/z: 319.2 (M+H)⁺.

(3S,5R)-1-(5-Fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3-sulfonamideor(3R,5S)-1-(5-fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3-sulfonamide,Example 37.5

Example 37.4 was separated by SFC on a Chiralpak AS-H column using 15%MeOH/CO₂. Example 37.5 and Example 37.6 are a pair of enantiomers,Example 37.5 was the second peak among 4 isomers (earlier peak vs. itsopposite enantiomer) on the AS-H column. ¹H NMR (400 MHz, CD₃OD) δ 1.96(ddd, J=13.39, 12.45, 2.93 Hz, 1H) 2.44 (dt, J=13.48, 1.89 Hz, 1H) 2.97(dd, J=14.33, 1.58 Hz, 1H) 3.08 (dd, J=13.01, 11.14 Hz, 1H) 3.28-3.35(m, 1H) 3.60-3.72 (m, 1H) 4.87-5.00 (m, 1H) 5.16 (dt, J=13.02, 1.91 Hz,1H) 8.27 (d, J=0.67 Hz, 2H). LCMS-ESI (pos.) m/z: 319.2 (M+H)⁺.

(3S,5R)-1-(5-Fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3-sulfonamideor(3R,5S)-1-(5-fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3-sulfonamide,Example 37.6

Further elution under the conditions described in Example 37.5 gaveExample 37.6 as the third peak. ¹H NMR (400 MHz, CD₃OD) δ 1.96 (ddd,J=13.39, 12.45, 2.93 Hz, 1H) 2.44 (dt, J=13.48, 1.89 Hz, 1H) 2.97 (dd,J=14.33, 1.58 Hz, 1H) 3.08 (dd, J=13.01, 11.14 Hz, 1H) 3.28-3.35 (m, 1H)3.60-3.72 (m, 1H) 4.87-5.00 (m, 1H) 5.16 (dt, J=13.02, 1.91 Hz, 1H) 8.27(d, J=0.67 Hz, 2H). LCMS-ESI (pos.) m/z: 319.2 (M+H)⁺.

(3R,5R)-1-(5-Fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3-sulfonamideor(3S,5S)-1-(5-fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3-sulfonamide,Example 37.7

Examples 37.7 and 37.8 are a pair of enantiomers. Example 37.7 was thefirst peak among 4 isomers (earlier peak vs. its opposite enantiomer) toelute on an AS-H column under the conditions described in Example 37.5.¹H NMR (400 MHz, CD₃OD) δ 0.92 (d, J=6.12 Hz, 3H) 1.08 (d, J=6.01 Hz,3H) 1.98 (ddd, J=13.19, 12.15, 2.95 Hz, 1H) 2.33 (dtdd, J=13.26, 3.68,3.68, 1.97, 1.87 Hz, 1H) 3.01 (dd, J=14.10, 1.66 Hz, 1H) 3.13 (dd,J=13.06, 10.99 Hz, 1H) 3.33-3.45 (m, 1H) 3.74 (dt, J=12.13, 6.06 Hz, 1H)3.86-3.93 (m, 1H) 4.77-4.83 (m, 1H) 5.11 (ddt, J=13.05, 3.69, 1.79, 1.79Hz, 1H) 8.27 (d, J=0.62 Hz, 2H). LCMS-ESI (pos.) m/z: 319.2 (M+H)⁺.

(3R,5R)-1-(5-Fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3-sulfonamideor(3S,5S)-1-(5-fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3-sulfonamide,Example 37.8

Further elution under the conditions described in Example 37.5 gaveExample 37.8 as the fourth peak. ¹H NMR (400 MHz, CD₃OD) δ 0.92 (d,J=6.12 Hz, 3H) 1.08 (d, J=6.01 Hz, 3H) 1.98 (ddd, J=13.19, 12.15, 2.95Hz, 1H) 2.33 (dtdd, J=13.26, 3.68, 3.68, 1.97, 1.87 Hz, 1H) 3.01 (dd,J=14.10, 1.66 Hz, 1H) 3.13 (dd, J=13.06, 10.99 Hz, 1H) 3.33-3.45 (m, 1H)3.74 (dt, J=12.13, 6.06 Hz, 1H) 3.86-3.93 (m, 1H) 4.77-4.83 (m, 1H) 5.11(ddt, J=13.05, 3.69, 1.79, 1.79 Hz, 1H) 8.27 (d, J=0.62 Hz, 2H).LCMS-ESI (pos.) m/z: 319.2 (M+H)⁺.

Example 38.0. Preparation of (S)-tert-butyl3-sulfamoylpiperidine-1-carboxylate and (R)-tert-butyl3-sulfamoylpiperidine-1-carboxylate

(S)-Piperidine-3-sulfonamide hydrochloride and(R)-piperidine-3-sulfonamide hydrochloride, Example 38.1

A solution of 4-chloropyridine-3-sulfonamide (5.0 g, 25.9 mmol) in AcOH(150 mL) was placed in a Parr bottle. The solution was bubbled withnitrogen gas for 5 mins. To this solution was added a suspension ofplatinum (IV) oxide (5.9 g, 25.9 mmol) in AcOH (30 mL). The reaction wasstirred under hydrogen (50 psi) for 72 h. The reaction mixture was thenfiltered through a pad of Celite® brand filter aid and the pad waswashed with MeOH (2×50 mL). The combined filtrate was concentrated invacuo to provide initial Example 38.1 (6.0 g) as an oil which was usedin the next step without further purification. LCMS-ESI (pos.) m/z: 165(M+H)⁺.

(S)-tert-Butyl 3-sulfamoylpiperidine-1-carboxylate and (R)-tert-butyl3-sulfamoylpiperidine-1-carboxylate, Example 38.0

To a mixture of 38.1 (12.0 g, 59.8 mmol) and TEA (41.6 mL, 298.9 mmol)in DCM (215 mL) was added a solution of boc anhydride (15.7 mL, 71.8mmol) in DCM (70 mL) at RT. The reaction mixture was stirred for 16 h atRT. The reaction mixture was washed with water (2×200 mL). The combinedorganic layer was washed with brine (100 mL), dried over sodium sulfateand evaporated in vacuo to obtain the product which was purified bycolumn chromatography (silica: 100-200 mesh; elution: 0-30% EtOAc inDCM) to provide the title compound—(4.6 g, 34%, over two steps) as awhite solid. ¹H NMR (400 MHz, CD₃CN) δ 5.30 (s, 2H), 4.36 (d, J=11.8 Hz,1H), 3.94 (d, J=13.3 Hz, 1H), 3.01-2.84 (m, 2H), 2.64-2.58 (s, 1H), 2.20(d, J=13.3 Hz, 1H), 1.78 (d, J=13.5 Hz, 1H), 1.74-1.57 (m, 2H), 1.43 (s,9H). LCMS-ESI (pos.) m/z: 263 (M−H)⁺.

Example 39.0: Preparation of(3S,5S)-1-(5-fluoropyrimidin-2-yl)-5-hydroxypiperidine-3-sulfonamide and(3S,5R)-1-(5-fluoropyrimidin-2-yl)-5-hydroxypiperidine-3-sulfonamide and(3R,5S)-1-(5-fluoropyrimidin-2-yl)-5-hydroxypiperidine-3-sulfonamide and(3R,5R)-1-(5-fluoropyrimidin-2-yl)-5-hydroxypiperidine-3-sulfonamide

5-Hydroxypyridine-3-sulfonamide, Example 39.1

To a 100 mL round-bottom flask was added 5-bromopyridine-3-sulfonamide(commercially available from Enamine, KIEV, Ukraine) (0.486 g, 2.05mmol),2-di-t-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-tri-i-isopropylbiphenyl(commercially available from Strem Chemicals, Inc., MA, USA) (0.079 g,0.16 mmol) and Pd₂(dba)₃ (Sigma-Aldrich Chemical Company, Inc.) (0.038g, 0.041 mmol). The flask was placed under vacuum and back-filled withpotassium hydroxide (0.345 g, 6.15 mmol) solution in dioxane (5 mL) andwater (5 mL). The reaction mixture was then stirred at 100° C. under N₂for 17 h. LCMS analysis indicated the reaction was complete. Thereaction mixture was allowed to cool to RT. The reaction mixture wasthen diluted with 1 N HCl and washed with Et₂O. The aqueous phase wasconcentrated in vacuo to afford the title compound 39.1 (0.387 g, 2.22mmol, 100% yield) as a white solid, which was used directly in the nextstep without further purification. LCMS-ESI (pos.), m/z: 175.1 (M+H)⁺.

(3R,5R)-5-Hydroxypiperidine-3-sulfonamide acetate and(3S,5R)-5-hydroxypiperidine-3-sulfonamide acetate and(3R,5S)-5-hydroxypiperidine-3-sulfonamide acetate and(3S,5S)-5-hydroxypiperidine-3-sulfonamide acetate, Example 39.2

To a 1 L hydrogenation flask was added 39.1 (6.46 g, 37.1 mmol) and AcOH(250 mL, 4330 mmol). Water (20 mL) was added as a co-solvent. Themixture was bubbled with N₂ for 2 min before platinum (iv) oxide hydrate(8.42 g, 37.1 mmol) was added under N₂ flow. The flask was set up on aParr shaker, vacuumed and back-filled with N₂ two times, and then placedunder vacuum and back-filled with hydrogen gas (tank). The reactionmixture was stirred at RT under 50 psi of hydrogen gas for 24 h. LCMSanalysis indicated that the reaction was complete. Celite® brand filteragent (20 g) was added to the mixture with stirring. The solid wasremoved by filtration after 10 min of stirring. The filter cake was thenrinsed with MeOH. The combined organics were concentrated in vacuo toafford 39.2 (8.91 g, 100% yield) as a light-yellow oil, which wasdirectly used in the next step without purification. LCMS-ESI (pos.),m/z: 181.1 (M+H)⁺.

(3S,5S)-1-(5-Fluoropyrimidin-2-yl)-5-hydroxypiperidine-3-sulfonamide and(3S,5R)-1-(5-fluoropyrimidin-2-yl)-5-hydroxypiperidine-3-sulfonamide and(3R,5S)-1-(5-fluoropyrimidin-2-yl)-5-hydroxypiperidine-3-sulfonamide and(3R,5R)-1-(5-fluoropyrimidin-2-yl)-5-hydroxypiperidine-3-sulfonamide,Example 39.0

To a 500 mL round-bottom flask was added 39.2 (8.91 g, 37.1 mmol) andHunig's base (32.3 mL, 185 mmol) in DMF (80 mL).2-Chloro-5-fluoro-pyrimidine (18.32 mL, 148 mmol) was then added withstirring. The reaction mixture was stirred at 120° C. for 18 h. LCMSanalysis indicated the reaction was complete. The reaction mixture wasallowed to cool to RT and then was diluted with water and extracted withDCM. The organic layers were washed with brine and dried over Na₂SO₄.The solution was filtered and concentrated in vacuo to give the initialmaterial as an orange oil. The material thus obtained was purified bysilica gel chromatography (a gradient of 0-100% EtOAc in DCM), toprovide 39.0 (3.7 g, 10.93 mmol, 36% yield) as a light-yellow solid.LCMS-ESI (pos.), m/z: 277.0 (M+H)⁺.

Example 40.3. Preparation of(3S,5R)-1-(5-fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide and(3R,5S)-1-(5-fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide

5-Methoxypyridine-3-sulfonamide, Example 40.1

The reaction mixture of 5-methoxypyridine-3-sulfonyl chloride(commercially available from Enamine, KIEV, Ukraine) (1.0 g, 4.82 mmol)and ammonia, (0.5 M solution in 1,4-dioxane, 96 mL, 48.2 mmol) wasstirred at 0 to RT for 30 min. LCMS indicated the reaction was complete.The reaction was filtered and the cake was rinsed with dioxane. Thecombined solution was concentrated in vacuo to give the title compound(0.91 g, 100% yield) as a light yellow foam which was used as such inthe next step without purification. LCMS-ESI (pos.) m/z: 189.2 (M+H)⁺.

(3R,5R)-5-Methoxypiperidine-3-sulfonamide acetate and(3R,5S)-5-methoxypiperidine-3-sulfonamide acetate and(3S,5R)-5-methoxypiperidine-3-sulfonamide acetate and(3S,5S)-5-methoxypiperidine-3-sulfonamide acetate, Example 40.2

The solution of 5-methoxypyridine-3-sulfonamide (0.9 g, 4.78 mmol) inAcOH (31.9 mL) was bubbled with argon gas for 2 min before platinum (iv)oxide ((1.09 g, 4.78 mmol) was added under an argon stream. The reactionmixture was then stirred at RT under 45 psi of hydrogen gas for 38 h.The mixture was filtered and the filtrate was concentrated in vacuo togive the title compound (1.22 g, 100% yield) as a light yellow foamwhich was used as such in the next step. LCMS-ESI (pos.) m/z: 195.2(M+H)⁺.

(3S,5R)-1-(5-Fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide and(3R,5S)-1-(5-fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide,Example 40.3

To a 40 mL vial (with pressure release septa) was added5-methoxypiperidine-3-sulfonamide acetate, 40.2 (2.45 g, 9.62 mmol),N-ethyl-N-isopropylpropan-2-amine (16.75 mL, 96 mmol) and2-chloro-5-fluoropyrimidine (6.37 g, 48.1 mmol) in DMSO (48 mL). Thereaction mixture was then stirred at 100° C. for 23 h. LCMS indicatedformation of the desired product. The reaction mixture was diluted withwater and extracted with DCM. The organic extract was washed withsaturated aqueous NaCl, brine and dried over Na₂SO₄. The solution wasfiltered and concentrated in vacuo to give the initial material as anorange oil. The initial material was absorbed onto a plug of silica geland purified by chromatography through a RediSep-Sep pre-packed silicagel column (40 g), eluting with a gradient of 0% to 100% 1/3 EtOH/EtOAcin heptanes to provide the title compound, 40.3 (0.51 g, 18% yield) aswhite solid, LCMS-ESI (pos.) m/z: 291.0 (M+H)⁺.

(3S,5S)-1-(5-Fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide and(3R,5R)-1-(5-fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide,Example 40.4

Further elution under the conditions described in Example 40.3 delivered40.4 (0.24 g, 0.832 mmol, 8.65% yield) as a light yellow solid. LCMS-ESI(pos.) m/z: 291.0 (M+H)⁺.

(3S,5R)-1-(5-Fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide or(3R,5S)-1-(5-fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide,Example 40.5

Example 40.5 was obtained by chiral separation of 40.3 on SFC: ChiralpakAD-H column, 30% MeOH/CO₂, with 0.2% DEA. Example 40.5 was the earlierpeak to elute on the Chiralpak AD-H column. ¹H NMR (400 MHz, CD₃OD) δ1.65 (td, J=12.28, 10.88 Hz, 1H) 2.57-2.72 (m, 2H) 2.98 (dd, J=13.06,11.40 Hz, 1H) 3.14 (ddt, 1H) 3.27-3.36 (m, 1H) 3.45 (s, 3H) 4.97 (ddt,1H) 5.17 (ddt, 1H) 8.32 (d, J=0.62 Hz, 2H). LCMS-ESI (pos.) m/z: 291.0(M+H)⁺.

(3S,5R)-1-(5-Fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide or(3R,5S)-1-(5-fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide,Example 40.6

Further elution under the conditions described in Example 40.5 deliveredExample 40.6. ¹H NMR (400 MHz, CD₃OD) δ 1.65 (td, J=12.28, 10.88 Hz, 1H)2.57-2.71 (m, 2H) 2.94-3.04 (m, 1H) 3.14 (ddt, 1H) 3.31-3.36 (m, 1H)3.45 (s, 3H) 4.97 (ddt, 1H) 5.17 (ddt, 1H) 8.32 (s, 2H). LCMS-ESI (pos.)m/z: 291.0 (M+H)⁺.

(3S,5S)-1-(5-Fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide or(3R,5R)-1-(5-fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide,Example 40.7

Example 40.7 was obtained by chiral separation of 40.4 on a SFC:Chiralpak AD-H column, 25% MeOH/CO₂, with 0.2% DEA. Example 40.7 was theearlier peak to elute on the Chiralpak AD-H column. ¹H NMR (400 MHz,CD₃OD) δ 1.98 (ddd, J=13.42, 12.39, 3.01 Hz, 1H) 2.41-2.51 (m, 1H) 2.98(dd, J=14.31, 1.66 Hz, 1H) 3.10 (dd, J=13.06, 11.20 Hz, 1H) 3.29-3.36(m, 1H) 3.32 (s, 3H) 3.66-3.71 (m, 1H) 4.98 (dq, J=14.38, 2.19 Hz, 1H)5.18 (ddt, 1H) 8.29 (d, J=0.83 Hz, 2H) LCMS-ESI (pos.) m/z: 291.0(M+H)⁺.

(3R,5R)-1-(5-Fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide or(3S,5S)-1-(5-fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide,Example 40.8

Further elution under the conditions described in Example 40.6 deliveredExample 40.8. ¹H NMR (400 MHz, CD₃OD) δ 1.96 (ddd, J=13.39, 12.45, 2.93Hz, 1H) 2.44 (dt, J=13.48, 1.89 Hz, 1H) 2.97 (dd, J=14.33, 1.58 Hz, 1H)3.08 (dd, J=13.01, 11.14 Hz, 1H) 3.28-3.35 (m, 1H) 3.32 (s, 3H)3.60-3.72 (m, 1H) 4.87-5.00 (m, 1H) 5.16 (dt, J=13.02, 1.91 Hz, 1H) 8.27(d, J=0.67 Hz, 2H). LCMS-ESI (pos.) m/z: 291.0 (M+H)⁺.

Example 41.0. Preparation of Examples(1R,2S)-1-ethoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide and(1S,2R)-1-ethoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide

(1R,2S)-1-Ethoxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamideand(1S,2R)-1-ethoxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide,Example 41.1

To a −78° C. solution of 34.5 (1.62 g, 3.4 mmol) in THF (70 mL) wasadded potassium bis(trimethylsilyl)amide (1.0 M solution in THF, 10.6mL, 10.6 mmol) slowly via syringe. After 1.25 h, ethyltrifluoromethanesulfonate (1.4 mL, 10.6 mmol) was added slowly viasyringe. The resulting orange solution was stirred at −78° C. for 45 minand then was quenched with a 2:1 mixture of saturated aqueous ammoniumchloride solution and water (75 mL). The resulting mixture was extractedwith EtOAc (4×). The combined organic layers were dried over anhydroussodium sulfate and concentrated in vacuo. The residue was purified bysilica gel chromatography (eluent: 10-65% EtOAc in hexanes) to provide41.1 (1.02 g, 60% yield) as a light yellow oil. LCMS-ESI (pos.) m/z:500.1 (M+H)⁺.

(1R,2S)-1-Ethoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide and(1S,2R)-1-ethoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide,Example 41.0

Example 41.1 (1.02 g, 2.0 mmol) was dissolved in TFA (14 mL) and anisole(466 μL, 4.3 mmol) was added via syringe. The resulting orange solutionwas stirred at RT for 16.5 h and was then concentrated in vacuo. Theresidue was purified by silica gel chromatography (eluent: pure DCMgrading to 4.5% MeOH in DCM) to provide the title compound Example 41.0(495 mg, 93% yield) as a white solid. LCMS-ESI (pos.) m/z: 260.0 (M+H)⁺.

The compounds set forth in the following table were synthesizedfollowing the procedure in Example 41.0 using the known startingmaterial as described.

TABLE 8 Example Reagents Structure, Name and Data 41.2

Ths material prepared in an analogous manner to that of Example 34.2employing the cis olefin.

(1R,2R)-1-ethoxy-1-(5- methylpyrimidin-2-yl)propane-2- sulfonamide and(1S,2S)-1-ethoxy-1- (5-methylpyrimidin-2-yl)propane-2- sulfonamide.LCMS-ESI (pos.) m/z: 260.0 (M + H)⁺. 115.0 5-chloropicolinaldehyde(commercially available from Combi-Blocks), methyltrifluoromethanesulfonate (commercially available from Combi-Blocks).

(1R,2S)-1-(5-chloropyridin-2-yl)-1- methoxypropane-2-sulfonamide and(1S,2R)-1-(5-chloropyridin-2-yl)-1- methoxypropane-2-sulfonamide.LCMS-ESI (pos.) m/z: 265.0 (M + H)⁺. 116.0 Example 116.0 was purified bypreparative SFC using the following method: Column: Chiral Pak IC (250 ×4.6) mm 5u, Mobile Phase: 0.1% DEA in hexanes: EtOH (80:20), Flow: 1.0mL/min. to provide peak 1.

(1R,2S)-1-(5-chloropyridin-2-yl)-1- methoxypropane-2-sulfonamide or(1S,2R)-1-(5-chloropyridin-2-yl)-1- methoxypropane-2-sulfonamide. ¹H NMR(400 MHz, DMSO-d₆) δ 8.64 (d, J = 2.5 Hz, 1H), 7.99 (dt, J = 8.4, 2.3Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 6.81 (s, 2H), 4.89 (d, J = 2.5 Hz,1H), 3.33 (m, 4H), 1.10 (dd, J = 7.0, 1.9 Hz, 3H). LCMS-ESI (pos.) m/z:265.0 (M + H)⁺. 117.0 Example 117.0 was purified by preparative SFCusing the following method: Column: CHIRAL PAK IC (250 × 4.6) mm 5u,Mobile Phase: 0.1% DEA in hexane: EtOH (80:20), Flow: 1.0 mL/min. toprovide peak 2.

(1R,2S)-1-(5-chloropyridin-2-yl)-1- methoxypropane-2-sulfonamide or(1S,2R)-1-(5-chloropyridin-2-yl)-1- methoxypropane-2-sulfonamide. ¹H NMR(400 MHz, DMSO-d₆) δ 8.64 (d, J = 2.4 Hz, 1H), 7.99 (dd, J = 8.3, 2.4Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 6.81 (s, 2H), 4.89 (d, J = 2.3 Hz,1H), 3.33 (m, 4H), and 1.10 (d, J = 7.0 Hz, 3H). LCMS-ESI (pos.) m/z:265.0 (M + H)⁺.

Example 42.0. Preparation of(1R,2S)—N-(1-cubane-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-(5-chloro-2-pyrimidinyl)-1-methoxy-2-propanesulfonamide

Methyl cubane-1-carboxylate, Example 42.1

To a solution of cubane-1-carboxylic acid (Pharmablock, 0.5 g, 3.37mmol) in MeOH (6.75 mL) was added sulfuric acid (0.018 mL, 0.34 mmol),and the reaction was heated at 60° C. for 4 h after which LCMS indicatedcomplete conversion to product. The solvent was removed in vacuo and themixture was dissolved in DCM, washed with a saturated solution ofNaHCO₃, dried over Na₂SO₄, and concentrated in vacuo to yield methylcubane-1-carboxylate (0.525 g, 3.24 mmol, 96% yield). ¹H NMR (500 MHz,CDCl₃) δ 4.21-4.30 (m, 3H) 3.95-4.07 (m, 4H) 3.68-3.74 (m, 3H). LCMS-ESI(pos.) m/z: 163.2 (M+H)⁺.

Cubane-1-carbohydrazide, Example 42.2

To methyl cubane-1-carboxylate (0.52 g, 3.21 mmol) in MeOH (4.86 mL) wasadded hydrazine, monohydrate (0.494 mL, 6.41 mmol), and the reaction washeated at 60° C. for 5 h. After 5 h, LCMS indicated complete conversionto the hydrazide. EtOAc was added, and the mixture was stirred at RT for1 h resulting in a white precipitate. The mixture was filtered and thefiltrate was washed with heptanes/EtOAc (1:1) to yieldcubane-1-carbohydrazide (0.52 g, 3.21 mmol, 100% yield). ¹H NMR (400MHz, CDCl₃) δ 6.62-6.87 (m, 1H) 4.19-4.28 (m, 3H) 3.99-4.08 (m, 4H).LCMS-ESI (pos.) m/z: 163.2 (M+H)⁺.

(Z)—N-(((1R,2R)-2-(5-Chloropyrimidin-2-yl)-1-methoxypropyl)sulfonyl)-2-(cubane-1-carbonyl)-N′-(4,6-dimethoxypyrimidin-5-yl)hydrazinecarboximidamide,Example 42.3

To a solution of(1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2-sulfonamide(Example 29.3, 0.2 g, 0.75 mmol) in ACN (7.53 mL) was added5-isothiocyanato-4,6-dimethoxypyrimidine (Example 28.1, 0.148 g, 0.75mmol) and cesium carbonate (0.312 g, 0.98 mmol). The resulting mixturewas then stirred at RT. After 12 h, LCMS showed complete consumption ofSM and conversion to the thiourea intermediate. To this white slurry wasadded cubane-1-carbohydrazide (Example 42.2, 0.122 g, 0.75 mmol)followed by silver(I) nitrate (0.256 g, 1.51 mmol), and the resultingmixture was stirred at RT. After 30 min, the mixture had turned brownand LCMS indicated conversion to product. The mixture was loadeddirectly onto silica gel and purified (30-100% EtOAc:EtOH 3:1 inheptanes) to yield the desired product as an off white solid (0.4 g,0.68 mmol, 90% yield).

(1R,2S)—N-(1-Cubane-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-(5-chloro-2-pyrimidinyl)-1-methoxy-2-propanesulfonamide,Example 42.0

To a solution of Example 42.3 (0.4 g, 0.677 mmol) in IPA (2.26 mL) andwater (1.123 mL) was added a solution of sodium hydroxide (1.0 M, 0.880mL, 0.880 mmol). The resulting mixture was then heated at 80° C. After 2h, the reaction was complete as determined by by LCMS. The mixture wasneutralized to pH 7 with 1.0 N HCl, extracted with DCM, dried oversodium sulfate and concentrated in vacuo. The product was purified bysilica gel 30-100% (EtOH:EtOAc 1:3 in heptanes) to yield Example 42.0(0.32 g, 0.56 mmol, 83% yield). ¹H NMR (400 MHz, CDCl₃) δ 10.77 (br s,1H) 8.69-8.75 (m, 2H) 8.47-8.53 (m, 1H) 5.29-5.32 (m, 1H) 4.90-4.97 (m,1H) 4.07-4.12 (m, 3H) 4.00-4.05 (m, 6H) 3.92-3.99 (m, 1H) 3.85-3.91 (m,3H) 3.68-3.77 (m, 1H) 3.33-3.37 (m, 3H) 1.34-1.40 (m, 3H). LCMS-ESI(pos.) m/z: 573.2 (M+H)⁺.

The compounds set forth in the following table were synthesizedfollowing the procedure in Example 42.0 using the known startingmaterial as described.

TABLE 9 Example Reagents Structure, Name and Data 42.4 1-(pyridin-2-yl)cyclopropane- carboxylic acid (commercially available from SigmaAldrich).

1-(pyridin-2- yl)cyclopropanecarbohydrazide. LCMS-ESI (pos.) m/z: 178.2(M + H)⁺. 42.5 1-(pyridin-2- yl)cyclobutane- carboxylic acid HCl(commercially available from AstaTech, Inc.).

1-(pyridin-3-yl)cyclobutanecarbohydrazide. LCMS-ESI (pos.) m/z: 192.2(M + H)⁺.

Following the procedure in Example 42.0 the following compounds may besynthesized using the intermediates and conditions described in thefollowing table.

TABLE 10 Example Reagents Structure, Name and Data 43.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and trans-2- fluorocyclopropanecarbohydrazide (material may beprepared in an analogous manner to that of Example 42.2 employing trans-2-fluoro-cyclopropanecarboxylic acid ethyl ester (commercially availablefrom Oakwood Chemical).

(1R,2S)-1-(5-chloropyrimidin-2-y1)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1R,2S)-2-fluorocyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1S,2R)-2-fluorocyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 44.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 2,2- difluorocyclopropanecarbohydrazide (material may beprepared in an analogous manner to that of Example 42.2 employing 2,2-difluorocyclopropanecarboxylic acid (commercially available fromEnamine).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((R)-2,2-difluorocyclopropyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide and(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((S)-2,2-difluorocyclopropyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 45.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2- sulfonamide (Example 29.3), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1), and 2-(trifluoromethyl)- cyclopropanecarbohydrazide (material may be preparedin an analogous manner to that of Example 42.2 employing2-(trifluoromethyl) cyclopropanecarboxylic acid (commercially availablefrom Enamine).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1S,2S)-2-(trifluoromethyl)cyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1R,2R)-2-(trifluoromethyl)cyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-(1R,2S)-2-(trifluoromethyl)cyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1S,2R)-2-(trifluoromethyl)cyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 46.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 2,2-difluoro-3- methylcyclopropanecarbohydrazide (materialmay be prepared in an analogous manner to that of Example 42.2 employing2,2- difluoro-3- methylcyclopropanecarboxylic acid (commerciallyavailable from Enamine).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1S,3R)-2,2-difluoro-3-methylcyclopropyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1R,3S)-2,2-difluoro-3-methylcyclopropyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide and(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1R,3R)-2,2-difluoro-3-methylcyclopropyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1S,3S)-2,2-difluoro-3-methylcyclopropyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide. 47.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 2-(difluoromethyl)- cyclopropanecarbohydrazide (material maybe prepared in an analogous manner to that of Example 42.2 employing2-(difluoromethyl)- cyclopropanecarboxylic acid (commercially availablefrom Enamine).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1S,2S)-2-(difluoromethyl)cyclopropyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1R,2R)-2-(difluoromethyl)cyclopropyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1R,2S)-2-(difluoromethyl)cyclopropyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1S,2R)-2-(difluoromethyl)cyclopropyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 48.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2- sulfonamide (Example 29.3), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1), and1-(2,2-difluoroethyl)- cyclopropanecarbohydrazide (material may beprepared in an analogous manner to that of Example 42.2 employing1-(2,2-difluoroethyl)-

cyclopropanecarboxylic (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-(1-(2,2-acid (commercially availabledifluoroethyl)cyclopropyl)-4-(4,6-dimethoxypyrimidin- from Enamine).5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide. 49.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 1-(trifluoromethyl)- cyclopropanecarbohydrazide (material maybe prepared in an analogous manner to that of Example 42.2 employing 1-(trifluoromethyl)-

cyclopropanecarboxylic (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-acid (commercially dimethoxypyrimidin-5-yl)-5-(1- available fromEnamine). (trifluoromethyl)cyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 52.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2- sulfonamide (Example 29.3), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1), and3,3-difluoro-1- methylcyclobutanecarbohydrazide (material may beprepared in an analogous manner to that of Example 42.2 employing ethyl3,3-difluoro-1-

methylcyclobutanecarboxylate(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-(3,3-difluoro- (commerciallyavailable from 1-methylcyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-PharmaBlock). 4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide.54.0 (1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 3- hydroxycyclobutanecarbohydrazide (material may be preparedin an analogous manner to that of Example 42.2 employing ethyl 3-hydroxycyclobutanecarboxylate (commercially available from Synthonix).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1s,3S)-3-hydroxycyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1r,3R)-3-hydroxycyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 55.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 3- hydroxycyclobutanecarbohydrazide (material may be preparedin an analogous manner to that of Example 42.2 employing ethyl 3-hydroxycyclobutanecarboxylate (commercially available from Synthonix).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1s,3S)-3-(hydroxymethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1r,3R)-3-(hydroxymethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 55.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 3- hydroxycyclobutanecarbohydrazide (material may be preparedin an analogous manner to that of Example 42.2 employing ethyl 3-hydroxycyclobutanecarboxylate (commercially available from Synthonix).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1s,3S)-3-(hydroxymethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1r,3R)-3-(hydroxymethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 56.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 3- oxocyclobutanecarbohydrazide (material may be prepared inan analogous manner to that of Example 42.2 employing methyl3-oxocyclobutanecarboxylate

(commercially available from(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6- Combi-Blocks Inc).dimethoxypyrimidin-5-yl)-5-(3-oxocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 57.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 3- cyanocyclobutanecarbohydrazide (material may be preparedin an analogous manner to that of Example 42.2 employing methyl3-cyanocyclobutanecarboxylate (commercially available from AstaTech,Inc). Methansulfonic acid will be used instead of sodium hydroxide.

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1s,3S)-3-cyanocyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide and(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1r,3S)-3-cyanocyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 58.0 This compound has been prepared (seeExample 179.0, Example 180.0, Example 181.0, and Example 182.0).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1R,2S)-2-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1- methoxypropane-2-sulfonamideand (1R,2S)-1-(5- chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1S,2R)-2-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1S,2S)-2-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1- methoxypropane-2-sulfonamideand (1R,2S)-1-(5- chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1R,2R)-2-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 59.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 1- fluorocyclobutanecarbohydrazide (material may be preparedin an analogous manner to that of Example 42.2 employing 1-fluorocyclobutanecarboxylic acid

(commercially available from(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6- Enamine).dimethoxypyrimidin-5-yl)-5-(1-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 60.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 1- hydroxycyclobutanecarbohydrazide (material may be preparedin an analogous manner to that of Example 42.2 employing 1-hydroxycyclobutanecarboxylic

acid (commercially available(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6- from Enamine).dimethoxypyrimidin-5-yl)-5-(1-hydroxycyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide. 61.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 4- (trifluoromethyl)bicyclo[1.1.1]- pentane-2-carbohydrazide(material may be prepared in an analogous manner to that of Example 42.2employing 4-

(trifluoromethyl)bicyclo[1.1.1]-(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6- pentane-2-carboxylic aciddimethoxypyrimidin-5-yl)-5-(4- (commercially available from(trifluoromethyl)bicyclo[1.1.1]pentan-2-yl)-4H-1,2,4- Enamine).triazol-3-yl)-1-methoxypropane-2-sulfonamide. 62.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 3- (difluoromethoxy)- cyclobutanecarbohydrazide (material maybe prepared in an analogous manner to that of Example 42.2 employing 3-(difluoromethoxy)- cyclobutanecarboxylic acid (commercially availablefrom Enamine).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1s,3S)-3-(difluoromethoxy)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1r,3S)-3-(difluoromethoxy)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 63.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2- sulfonamide (Example 29.3), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1), and2-(fluoromethyl)- cyclobutanecarbohydrazide (material may be prepared inan analogous manner to that of Example 42.2 2- (fluoromethyl)-cyclobutanecarboxylic acid (commercially available from Enamine).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1S,2S)-2-(fluoromethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1R,2R)-2-(fluoromethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1R,2S)-2-(fluoromethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1S,2R)-2-(fluoromethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 64.0 This compoundhas been prepared (See Example 146.0).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1S,2S)-2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1R,2R)-2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1R,25)-2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1S,2R)-2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 65.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2- sulfonamide (Example 29.3), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1), and1-(difluoromethyl)- cyclobutanecarbohydrazide (material may be preparedin an analogous manner to that of Example 42.2 employing 1-

(difluoromethyl)- (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-(1-cyclobutanecarboxylic (difluoromethyl)cyclobutyl)-4-(4,6- acid(commercially dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-available from Enamine). methoxypropane-2-sulfonamide. 66.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 1-(trifluoromethyl)- cyclobutanecarbohydrazide (material maybe prepared in an analogous manner to that of Example 42.2 employing 1-

(trifluoromethyl)- (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-cyclobutanecarboxylic dimethoxypyrimidin-5-yl)-5-(1- acid (commercially(trifluoromethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1- available fromEnamine). methoxypropane-2-sulfonamide. 67.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 2,2- difluorocyclobutane- carbohydrazide (material may beprepared in an analogous manner to that of Example 42.2 employing 2,2-difluorocyclobutanecarboxylic acid (commercially available fromEnamine).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((S)-2,2-difluorocyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide and(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((R)-2,2-difluorocyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 68.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2- sulfonamide (Example 29.3), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1), and 3,3-difluorocyclobutane- carbohydrazide (material may be prepared in ananalogous manner to that of Example 42.2 employing methyl

3,3- (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-(3,3-difluorocyclobutanecarboxylatedifluorocyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)- (commerciallyavailable from 4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- Enamine).sulfonamide. 69.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2- sulfonamide (Example 29.3), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1), and 1-hydroxycyclopentane- carbohydrazide (material may be prepared in ananalogous manner to that of Example 42.2 employing methyl

1- (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-hydroxycyclopentanecarboxylatedimethoxypyrimidin-5-yl)-5-(1-hydroxycyclopentyl)- (commerciallyavailable from 4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- AstaTech,Inc). sulfonamide. 70.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2- sulfonamide (Example 29.3), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1), and cyclopent-3-enecarbohydrazide (material may be prepared in an analogous manner tothat of Example 42.2 employing ethyl cyclopent-3- enecarboxylate(commercially

available from Oakwood).(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-(cyclopent-3-en-1-yl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 71.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 3,3- difluorocyclopentanecarbohydrazide (material may beprepared in an analogous manner to that of Example 42.2 employing 3,3-difluorocyclopentanecarboxylic acid (commercially available fromEnamine).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((S)-3,3-difluorocyclopentyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide and(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((R)-3,3-difluorocyclopentyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 72.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2- sulfonamide (Example 29.3), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1), and 2,2-difluorocyclopentanecarbohydrazide (material may be prepared in ananalogous manner to that of Example 42.2 employing 2,2-difluorocyclopentanecarboxylic acid (commercially available fromEnamine).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((S)-2,2-difluorocyclopentyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide and(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((R)-2,2-difluorocyclopentyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 73.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2- sulfonamide (Example 29.3), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1), and 3-methoxycyclopentanecarbohydrazide (material may be prepared in ananalogous manner to that of Example 42.2 employing 3-methoxycyclopentanecarboxylic acid (commercially available from Enamine)

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1S,3S)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1R,3R)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1R,3S)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1S,3R)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 74.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 1-(difluoromethyl)- cyclopentanecarbohydrazide (material maybe prepared in an analogous manner to that of Example 42.2 employing1-(difluoromethyl)-

cyclopentanecarboxylic (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-(1- acid(commercially available from Enamine).(difluoromethyl)cyclopentyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 75.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2- sulfonamide (Example 29.3), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1), and 3-fluorocyclopentanecarbohydrazide (material may be prepared in ananalogous manner to that of Example 42.2 employing 3-fluorocyclopentanecarboxylic acid (commercially available from Enamine).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1R,3R)-3-fluorocyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1S,3S)-3-fluorocyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1S,3R)-3-fluorocyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1R,3S)-3-fluorocyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 76.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and bicyclo[3.1.0]hexane- 3-carbohydrazide (material may beprepared in an analogous manner to that of Example 42.2 employingbicyclo[3.1.0]hexane- 3-carboxylic acid (commercially

available from Enamine). (1R,2S)-N-(5-(bicyclo[3.1.0]hexan-3-yl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2- sulfonamide. 77.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 2-(hydroxymethyl)- cyclohexanecarbohydrazide (material may beprepared in an analogous manner to that of Example 42.2 employing2-(hydroxymethyl)- cyclohexanecarboxylic acid (commercially availablefrom Oakwood).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1S,2S)-2-(hydroxymethyl)cyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1R,2R)-2-(hydroxymethyl)cyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1R,2S)-2-(hydroxymethyl)cyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1S,2R)-2-(hydroxymethyl)cyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 78.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 4-(hydroxymethyl)- cyclohexanecarbohydrazide (material may beprepared in an analogous manner to that of Example 42.2 employing4-(hydroxymethyl)- cyclohexanecarboxylic acid (commercially availablefrom Ark Pharm).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1s,4S)-4-(hydroxymethyl)cyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1r,4R)-4-(hydroxymethyl)cyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 79.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 2- hydroxycyclohexanecathohydrazide (material may be preparedin an analogous manner to that of Example 42.2 employing ethyl 2-hydroxycyclohexanecarboxylate (commercially available from Ark Pharm).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1R,2S)-2-hydroxycyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1S,2R)-2-hydroxycyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1S,2S)-2-hydroxycyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1R,2R)-2-hydroxycyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 80.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 4- oxocyclohexanecarbohydrazide (material may be prepared inan analogous manner to that of Example 42.2 employing tert- butyl 4-

oxocyclohexanecarboxylate (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-(commercially available fromdimethoxypyrimidin-5-yl)-5-(4-oxocyclohexyl)-4H- AstaTech).1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 81.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 4-(difluoromethoxy)- cyclohexanecarbohydrazide (material maybe prepared in an analogous manner to that of Example 42.2 employing4-(difluoromethoxy)- cyclohexanecarboxylic acid (commercially availablefrom Enamine).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1s,4S)-4-(difluoromethoxy)cyclohexyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1r,4R)-4-(difluoromethoxy)cyclohexyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. 98.0 (S)-1-(5-fluoropyrimidin-2-yl)piperidine-3-sulfonamide and (R)-1-(5-fluoropyrimidin-2-yl)piperidine-3-sulfonamide (Example 98.12), 2- isothiocyanato-1,3-dimethoxybenzene (Example 28.0), and cyclobutanecarbohydrazide(commercially available from ChemBridge Corporation).

(S)-N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2- yl)piperidine-3-sulfonamideand (R)-N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)piperidine-3-sulfonamide. 99.0(3S,5R)-l-(5-fluoropyrimidin-2- yl)-5-methoxypiperidine-3- sulfonamideand (3R,5S)-1-(5- fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide (Example 40.3), 2- isothiocyanato-1,3-dimethoxybenzene (Example 28.0), and cyclobutanecarbohydrazide(commercially available from ChemBridge Corporation).

(3S,5R)-N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide and (3R,5S)-N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)-5-methoxypiperidine- 3-sulfonamide.111.0 (1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2-sulfonamide (Example 29.3), 2- methoxyethyl isothiocyanate (commerciallyavailable from Sigma Aldrich), and cyclobutanecarbohydrazide(commercially available from ChemBridge Corporation).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-cyclobutyl-4-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-1- methoxypropane-2-sulfonamide.112.0 (1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2-sulfonamide (Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine(Example 28.1), and 2,2- dimethylcyclobutanecarbohydrazide (material maybe prepared in an analogous manner to that of Example 42.2 employing2,2- dimethylcyclobutanecarboxylic acid (commercially available fromLabNetwork).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((S)-2,2-dimethylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((R)-2,2-dimethylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide.

Example 98.1. Preparation of(R)-1-(5-fluoropyrimidin-2-yl)piperidine-3-sulfonamide and(S)-1-(5-fluoropyrimidin-2-yl)piperidine-3-sulfonamide

(±)-Piperidine-3-sulfonamide hydrochloride, Example 98.11

To a 100-mL round-bottomed flask was added4-chloro-3-pyridinesulfonamide (commercially available from Alfa Aesar,0.56 g, 2.91 mmol) in AcOH (25 mL). N₂ was bubbled through thesuspension for 5 mins before platinum (iv) oxide (commercially availablefrom Sigma-Aldrich, USA, 0.330 g, 1.454 mmol) was added under N₂ flow.The flask was then sealed with a septum and vacuumed. Hydrogen gas wasback-filled from a balloon. The reaction mixture was stirred at 23° C.under hydrogen gas for 3 days. Celite® brand filter aid (20 g) was thenadded to the reaction mixture with stirring. The solution was filteredthrough a short pad of Celite® brand filter aid. The cake was rinsedwith MeOH. The combined organics were concentrated in vacuo to give theinitial material as a light-yellow glass. The residue was trituratedwith DCM to afford Example 98.11 (0.6 g, 2.99 mmol, 103% yield) as alight yellow solid. LCMS-ESI (pos.), m/z: 165.2 (M+H)⁺.

(R)-1-(5-Fluoropyrimidin-2-yl)piperidine-3-sulfonamide and(S)-1-(5-fluoropyrimidin-2-yl)piperidine-3-sulfonamide, Example 98.12

To a 50-mL vial was added Example 98.11 (200 mg, 0.997 mmol) and2-chloro-5-fluoro-pyrimidine (Matrix Scientific, SC, USA, 0.66 mL, 4.98mmol) in DMSO (5 mL). Hunig's base (0.867 mL, 4.98 mmol) was then addedwith stirring. The reaction mixture was stirred at 100° C. for 2 h. LCMSanalysis indicated the reaction was complete. The reaction mixture wasallowed to cool to room temperature. The reaction mixture was thendiluted with water and extracted with DCM. The organic extract waswashed with brine and dried over Na₂SO₄. The solution was filtered andconcentrated in vacuo to give the initial material as a light-yellowglass, which was triturated with IPA to afford Example 98.12 (240 mg,93% yield) as an off-white solid. ¹H NMR (500 MHz, CDCl₃) δ 8.21 (s, 2H)4.98-5.07 (m, 1H) 4.76 (s, 2H) 4.49-4.59 (m, 1H) 3.31 (dd, J=12.96,10.27 Hz, 1H) 3.15 (tt, J=10.51, 3.91 Hz, 1H) 3.04 (ddd, J=13.69, 11.49,2.69 Hz, 1H) 2.32-2.43 (m, 1H) 1.87-2.02 (m, 2H) 1.51-1.63 (m, 1H).LCMS-ESI (pos.), m/z: 261.2 (M+H)⁺.

The compounds set forth in the following table were synthesizedfollowing the procedure in Example 42.0 using the known startingmaterial as described.

TABLE 11 100.0 (1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2-sulfonamide (Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine(Example 28.1), and (R)-2,2- difluorocyclopropanecarbohydrazidehydrochloride and (S)-2,2- difluorocyclopropanecarbohydrazidehydrochloride (Example 100.2). The racemic mixture was purified usingthe following preparative SFC method: Column: AS-H (2 × 15 cm) MobilePhase: 77:23 (A:B) A: Liquid CO₂, B: IPA, Flow Rate: 70 mL/min, 224 nm,100 bar inlet pressure to deliver Peak 1.

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((R)-2,2-difluorocyclopropyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((S)-2,2-difluorocyclopropyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ 13.18 (s, 1H),8.93 (s, 2H), 8.70 (s, 1H), 4.80 (d, J = 3.9 Hz, 1H), 4.00- 3.96 (m,3H), 3.96-3.94 (m, 3H), 3.47-3.36 (m, 1H), 3.12 (s, 3H), 3.02-2.93 (m,1H), 2.13-2.02 (m, 2H), 1.14 (d, J = 6.8 Hz, 3H). LCMS-ESI (pos.) m/z:547.0 (M + H)⁺. 101.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2- sulfonamide (Example 29.3), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1), and (R)-2,2-difluorocyclopropanecarbohydrazide hydrochloride and (S)-2,2-difluorocyclopropanecarbohydrazide hydrochloride (Example 100.2). Theracemic mixture was purified by using the following preparative SFCmethod: Column: AS-H (2 × 15 cm) Mobile Phase: 77:23 (A:B) A: LiquidCO₂, B: IPA, Flow Rate: 70 mL/min, 224 nm, 100 bar inlet pressure todeliver Peak 2.

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((R)-2,2-difluorocyclopropyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((S)-2,2-difluorocyclopropyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ = 13.16 (s,1H), 8.93 (s, 2H), 8.70 (s, 1H), 4.80 (d, J = 4.1 Hz, 1H), 3.97 (s, 3H),3.96-3.93 (m, 3H), 3.48-3.35 (m, 1H), 3.14 (s, 3H), 2.97 (q, J = 9.9 Hz,1H), 2.08 (q, J = 9.4 Hz, 2H), 1.16 (d, J = 6.8 Hz, 3H). LCMS-ESI (pos.)m/z: 547.0 (M + H)⁺. 102.0 (1R,2S)-1-(5-chloro-pyrimidin-2-yl)-1-methoxypropane-2- sulfonamide (Example 29.3), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1), and (S)-6-oxaspiro[2.5]octane-1- carbohydrazide and (R)-6- oxaspiro[2.5]octane-1-carbohydrazide (commercially available from Ukrorgsyntez). The racemicmixture was purified using the following preparative SFC method: Column:AD-H (2 × 25 cm) Mobile Phase: 76:24 (A:B) A: Liquid CO₂, B: IPA, FlowRate: 70 mL/min, 230 nm, 100 bar inlet pressure to deliver Peak 1.

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((R)-6-oxaspiro[2.5]octan-1-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((S)-6-oxaspiro[2.5]octan-1-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (400 MHz, DMSO-d₆)δ 12.89 (s, 1H), 8.93 (s, 2H), 8.72 (s, 1H), 4.80 (d, J = 3.7 Hz, 1H),4.03- 3.98 (m, 3H), 3.98-3.94 (m, 3H), 3.57-3.44 (m, 3H), 3.43-3.33 (m,2H), 3.12 (s, 3H), 1.55-1.48 (m, 1H), 1.47-1.40 (m, 1H), 1.38-1.24 (m,3H), 1.17-1.08 (m, 4H), 1.02-0.95 (m, 1H). LCMS-ESI (pos.) m/z: 581.2(M + H)⁺. 103.0 (1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2-sulfonamide (Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine(Example 28.1), and (S)-6- oxaspiro[2.5]octane-1- carbohydrazide and(R)-6- oxaspiro[2.5]octane-1- carbohydrazide (commercially availablefrom Ukrorgsyntez). The racemic mixture was purified using the followingpreparative SFC method: Column: AD-H (2 × 25 cm) Mobile Phase: 76:24(A:B) A: Liquid CO₂, B: IPA, Flow Rate: 70 mL/min, 230 nm, 100 bar inletpressure to deliver Peak 2.

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((R)-6-oxaspiro[2.5]octan-1-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((S)-6-oxaspiro[2.5]octan-1-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (400 MHz, DMSO-d₆)δ 12.88 (s, 1H), 8.93 (s, 2H), 8.72 (s, 1H), 4.78 (d, J = 3.9 Hz, 1H),4.01- 3.98 (m, 3H), 3.98-3.96 (m, 3H), 3.57-3.44 (m, 3H), 3.42-3.34 (m,2H), 3.12 (s, 3H), 1.51 (dd, J = 5.6, 8.5 Hz, 1H), 1.47-1.40 (m, 1H),1.36-1.24 (m, 3H), 1.17- 1.08 (m, 4H), 1.03-0.97 (m, 1H). LCMS-ESI(pos.) m/z: 581.2 (M + H)⁺. 105.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2- sulfonamide (Example 29.3), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1), and(R)-spiro[2.2]pentane- 1-carbohydrazide hydrochloride and(S)-spiro[2.2]pentane-1- carbohydrazide hydrochloride (Example 105.2).The racemic mixture was purified using the following preparative SFCmethod: Column: AD-H (3 × 25 cm) Mobile Phase: 85:15 (A:B) A: LiquidCO₂, B: MeOH, Flow Rate: 200 mL/min, 254 nm, 100 bar inlet pressure todeliver Peak 1.

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((R)-spiro[2.2]pentan-1-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamideor(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((S)-spiro[2.2]pentan-1-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ 12.84 (br s,1H), 8.93 (s, 2H), 8.68 (s, 1H), 4.77 (d, J = 4.1 Hz, 1H), 3.97 (s, 3H),3.92 (s, 3H), 3.43-3.35 (m, 1H), 3.14 (s, 3H), 1.93 (dd, J = 4.6, 7.9Hz, 1H), 1.49 (t, J = 4.3 Hz, 1H), 1.41 (dd, J = 4.1, 7.9 Hz, 1H), 1.14(d, J = 6.8 Hz, 3H), 0.89-0.83 (m, 1H), 0.82-0.73 (m, 2H), 0.70-0.65 (m,1H). LCMS-ESI (pos.) m/z: 537.2 (M + H)⁺. 106.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), (R)-spiro[2.2]pentane-1- carbohydrazide hydrochloride and(S)-spiro[2.2]pentane-1- carbohydrazide hydrochloride (Example 105.2).The racemic mixture was purified using the following preparative SFCmethod: Column: AD-H (3 × 25 cm) Mobile Phase: 85:15 (A:B) A: LiquidCO₂, B: MeOH, Flow Rate: 200 mL/min, 254 nm, 100 bar inlet pressure todeliver Peak 2.

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((R)-spiro[2.2]pentan-1-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((S)-spiro[2.2]pentan-1-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ = 12.85 (s,1H), 8.93 (s, 2H), 8.68 (s, 1H), 4.78 (d, J = 4.1 Hz, 1H), 3.96 (s, 3H),3.93 (s, 3H), 3.43-3.36 (m, 1H), 3.13 (s, 3H), 1.93 (dd, J = 4.5, 7.8Hz, 1H), 1.49 (t, J = 4.3 Hz, 1H), 1.41 (dd, J = 4.1, 7.9 Hz, 1H), 1.13(d, J = 7.0 Hz, 3H), 0.90-0.83 (m, 1H), 0.83-0.74 (m, 2H), 0.71-0.65 (m,1H). LCMS-ESI (pos.) m/z: 537.0 (M + H)⁺. 107.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and (1S,2R)-2- ethoxycyclopropanecarbohydrazide and (1S,2S)-2-ethoxycyclopropanecarbohydrazide and (1R,2R)-2-ethoxycyclopropanecarbohydrazide and (1R,2S)-2-ethoxycyclopropanecarbohydrazide (commercially available fromUkrorgsyntez). The mixture was purified using the following preparativeSFC method: Column: AD-H (2 × 25 cm), Mobile Phase: 75:25 (A:B) A:Liquid CO₂, B: MeOH, Flow Rate: 80 mL/min, 215 nm, 100 bar inletpressure to deliver Peak 1.

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,2R)-2-ethoxycyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1S,2S)-2-ethoxycyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,2S)-2-ethoxycyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1S,2R)-2-ethoxycyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (400 MHz, CD₂Cl₂) δ 10.97-10.34(m, 1H), 8.71 (s, 2H), 7.48 (t, J = 8.5 Hz, 1H), 6.76-6.71 (m, 2H), 4.86(d, J = 4.8 Hz, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 3.57 (dq, J = 4.8, 7.0Hz, 1H), 3.46-3.31 (m, 3H), 3.25 (s, 3H), 1.49-1.40 (m, 2H), 1.26 (d, J= 6.8 Hz, 3H), 1.11-1.02 (m, 4H). LCMS-ESI (pos.) m/z: 553.2 (M + H)⁺.108.0 (1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2-sulfonamide (Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine(Example 28.1), and (1S,2R)-2- ethoxycyclopropanecarbohydrazide and(1S,2S)-2- ethoxycyclopropanecarbohydrazide and (1R,2R)-2-ethoxycyclopropanecarbohydrazide and (1R,2S)-2-ethoxycyclopropanecarbohydrazide (commercially available fromUkrorgsyntez). The mixture was purified using the following preparativeSFC method: Column: AD-H (2 × 25 cm), Mobile Phase: 75:25 (A:B) A:Liquid CO₂, B: MeOH, Flow Rate: 80 mL/min, 215 nm, 100 bar inletpressure to deliver Peak 2.

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,2R)-2-ethoxycyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1S,2S)-2-ethoxycyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,2S)-2-ethoxycyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1S,2R)-2-ethoxycyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ =13.20-11.78 (m, 1H), 8.92 (s, 2H), 7.50 (t, J = 8.5 Hz, 1H), 6.87 (d, J= 8.5 Hz, 2H), 4.78 (d, J = 4.1 Hz, 1H), 3.76 (s, 3H), 3.72 (s, 3H),3.44-3.41 (m, 2H), 3.38-3.34 (m, 1H), 3.27- 3.22 (m, 1H), 3.15 (s, 3H),1.42-1.35 (m, 1H), 1.32- 1.27 (m, 1H), 1.14 (d, J = 7.0 Hz, 3H),1.10-1.04 (m, 1H), 0.98 (t, J = 7.0 Hz, 3H). LCMS-ESI (pos.) m/z: 553.0(M + H)⁺. 109.0 (1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2-sulfonamide (Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine(Example 28.1), and (1S,2R)-2- ethoxycyclopropanecarbohydrazide and(1S,2S)-2- ethoxycyclopropanecarbohydrazide and (1R,2R)-2-ethoxycyclopropanecarbohydrazide and (1R,2S)-2-ethoxycyclopropanecarbohydrazide (commercially available fromUkrorgsyntez). The mixture was purified using the following preparativeSFC method: Column: Chromega Chiral CC4 (3 × 15 cm) coupled withChromega Chiral CC4 (3 × 25 cm), Mobile Phase: 70:30 (A:B) A: LiquidCO₂, B: MeOH, Flow Rate: 140 mL/min, 220 nm, 100 bar inlet pressure todeliver Peak 1.

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,2R)-2-ethoxycyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1S,2S)-2-ethoxycyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,2S)-2-ethoxycyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1S,2R)-2-ethoxycyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ 12.66 (s,1H), 8.92 (s, 2H), 7.52 (t, J = 8.5 Hz, 1H), 6.87 (t, J = 7.6 Hz, 2H),4.76 (d, J = 4.4 Hz, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 3.44- 3.36 (m,1H), 3.31-3.28 (m, 1H), 3.20 (qd, J = 7.0, 9.5 Hz, 1H), 3.14 (s, 3H),2.99 (qd, J = 7.0, 9.5 Hz, 1H), 1.40-1.34 (m, 1H), 1.27-1.21 (m, 1H),1.20-1.15 (m, 1H), 1.14 (d, J = 7.0 Hz, 3H), 0.94 (t, J = 7.0 Hz, 3H).LCMS-ESI (pos.) m/z: 553.2 (M + H)⁺. 110.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and (1S,2R)-2- ethoxycyclopropanecarbohydrazide and (1S,2S)-2-ethoxycyclopropanecarbohydrazide and (1R,2R)-2-ethoxycyclopropanecarbohydrazide and (1R,2S)-2-ethoxycyclopropanecarbohydrazide (commercially available fromUkrorgsyntez). The mixture was purified using the following preparativeSFC method: Column: Chromega Chiral CC4 (3 × 15 cm) coupled withChromega Chiral CC4 (3 × 25 cm), Mobile Phase: 70:30 (A:B) A: LiquidCO₂, B: MeOH, Flow Rate: 140 mL/min, 220 nm, 100 bar inlet pressure todeliver Peak 2.

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,2R)-2-ethoxycyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1S,2S)-2-ethoxycyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,2S)-2-ethoxycyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1S,2R)-2-ethoxycyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ = 12.66 (brs, 1H), 8.92 (s, 2H), 7.52 (t, J = 8.5 Hz, 1H), 6.88 (d, J = 8.7 Hz,1H), 4.77 (d, J = 4.1 Hz, 1H), 3.81-3.77 (m, 3H), 3.77- 3.75 (m, 3H),3.43-3.36 (m, 1H), 3.31-3.29 (m, 1H), 3.21 (qd, J = 7.0, 9.5 Hz, 1H),3.14 (s, 3H), 3.05-2.96 (m, 1H), 1.40-1.35 (m, 1H), 1.26-1.21 (m, 1H),1.21- 1.16 (m, 1H), 1.13 (d, J = 7.0 Hz, 3H), 0.94 (t, J = 6.9 Hz, 3H).LCMS-ESI (pos.) m/z: 553.0 (M + H)⁺.

Example 100.2. Preparation of (R)-2,2-difluorocyclopropanecarbohydrazidehydrochloride and (S)-2,2-difluorocyclopropanecarbohydrazidehydrochloride

tert-Butyl 2-(2,2-difluorocyclopropanecarbonyl)hydrazinecarboxylateExample 100.1

A flask containing 2,2-difluorocyclopropanecarboxylic acid (1.01 g, 8.2mmol) (commercially available from Alfa Aesar, a Johnson Mathey Company)in anhydrous DCM (16.5 mL) was cooled in an ice bath. After 20 mins,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.62 g, 8.5mmol) and then tert-butyl carbazate (1.14 g, 8.6 mmol) were carefullyadded in portions to the homogeneous solution. Upon complete addition oftert-butyl carbazate, the solution was allowed to warm to RT. After 19h, the reaction was carefully quenched with water and then extractedthree times with DCM. The organic layers were pooled and then washedonce with brine. The organic layer was dried over anhydrous magnesiumsulfate and was then filtered and concentrated in vacuo. The colorlessfilm was identified as tert-butyl 2-(2,2-difluorocyclopropanecarbonyl)hydrazinecarboxylate, Example 100.1 (1.95 g, 8.2 mmol, 100% yield), andwas used without purification. ¹H NMR (400 MHz, CD₂Cl₂) 6=8.02-7.81 (m,1H), 6.72-6.53 (m, 1H), 2.44-2.34 (m, 1H), 2.15-2.08 (m, 1H), 1.80-1.73(m, 1H), 1.46 (s, 9H

(R)-2,2-Difluorocyclopropanecarbohydrazide hydrochloride and(S)-2,2-difluorocyclopropanecarbohydrazide hydrochloride Example 100.2

A flask containing tert-butyl2-(2,2-difluorocyclopropanecarbonyl)hydrazinecarboxylate (1.95 g, 8.2mmol) in EtOH (8.3 mL) was cooled in an ice water bath. After 20 mins,hydrogen chloride (EtOH solution 1.25 M in EtOH (26.5 mL, 33.1 mmol))was added carefully dropwise. Upon complete addition of acid, themixture was allowed to warm to RT. After 22 h, the reaction was dilutedwith EtOAc and then carefully concentrated in vacuo. The solid wassuspended in EtOAc and a few drops of EtOH. The subsequent white solidwas filtered and identified as Example 100.2 and was used withoutpurification. LCMS-ESI (pos.) m/z: 137.4 (M+H)⁺.

Example 105.2. Preparation of (R)-spiro[2.2]pentane-1-carbohydrazidehydrochloride and (S)-spiro[2.2]pentane-1-carbohydrazide hydrochloride

tert-Butyl 2-(spiro[2.2]pentane-1-carbonyl)hydrazinecarboxylate, Example105.1

A flask containing spiro[2.2]pentane-1-carboxylic acid (904 mg, 8.1mmol) (commercially available from ChemBridge) in anhydrous DCM (16 mL)was cooled in an ice bath. After 20 mins,N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, EDCI (1.55g, 8.1 mmol), and then tert-butyl carbazate (1.08 g, 8.15 mmol) werecarefully added in portions to the homogeneous solution. Upon completeaddition of tert-butyl carbazate, the homogeneous solution was allowedto warm to RT. After 22 h, the reaction was carefully quenched withwater and then extracted three times with DCM. The organic layers werepooled and then washed once with brine. The organic layer was dried overanhydrous magnesium sulfate and then filtered and concentrated in vacuo.The colorless residue was identified as Example 105.1 (1.8 g, 8.0 mmol,99% yield) that was used without purification. LCMS-ESI (pos.) m/z:225.3 (M−H)⁻.

(R)-Spiro[2.2]pentane-1-carbohydrazide hydrochloride and(S)-spiro[2.2]pentane-1-carbohydrazide hydrochloride, Example 105.2

A flask containing tert-butyl2-(spiro[2.2]pentane-1-carbonyl)hydrazinecarboxylate, Example 105.1 (1.8g, 8.0 mmol) in EtOH (8 mL), was cooled in an ice water bath. After 20mins, hydrogen chloride (1.25M in EtOH (32 mL, 32.0 mmol)) was addedcarefully dropwise. Upon complete addition of acid, the mixture wasallowed to warm to RT. After 19 h, the reaction was diluted with EtOAcand then carefully concentrated in vacuo. The white solid was suspendedin EtOAc and then sonicated. The subsequent white solid was filtered andidentified as Example 105.2 (1.11 g, 6.8 mmol, 86% yield) and was usedwithout purification. LCMS-ESI (pos.) m/z: 127.2 (M+H)⁺.

The compounds set forth in the following table were synthesizedfollowing the procedure in Example 42.0 using the known startingmaterial as described.

TABLE 12 Example Reagents Structure, Name and Data 82.0(1R,2S)-1-methoxy-1-(5- methylpyrazin-2-yl)propane-2- sulfonamide(Example 29.1), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and cyclobutanecarbohydrazide (commercially available fromChemBridge Corporation).

(1R,2S)-N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide. ¹H NMR (500 MHz, CDCl₃) δ10.73 (br s, 1H), 8.45- 8.55 (m, 3H), 5.04 (d, J = 2.85 Hz, 1H), 3.99(m, 6H), 3.51 (dq, J = 2.85, 7.01 Hz, 1H), 3.35 (s, 3H), 3.10 (quin, J =8.40 Hz, 1H), 2.58-2.62 (m, 3H), 2.29-2.39 (m, 2H), 2.04-2.13 (m, 2H),1.90-2.03 (m, 2H), 1.24 (d, J = 7.01 Hz, 3H). LCMS-ESI (pos.) m/z: 505.2(M + H)⁺. 83.0 (1S,2S)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane-2- sulfonamide (Example 31.0), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1), andcyclobutanecarbohydrazide (commercially available from ChemBridgeCorporation).

(1S,2S)-N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-1-(2-propanyloxy)-2- propanesulfonamide. ¹H NMR (500 MHz,CDCl₃) δ 12.47 (br s, 1H), 8.66 (s, 2H), 8.49 (s, 1H), 4.89 (d, J = 3.89Hz, 1H), 4.04 (s, 3H), 3.98 (s, 3H), 3.73 (dq, J = 3.96, 6.98 Hz, 1H),3.61 (spt, J = 6.06 Hz, 1H), 3.09 (quin, J = 8.24 Hz, 1H), 2.38- 2.46(m, 1H), 2.36 (s, 3H), 2.21-2.33 (m, 1H), 2.14 (ttd, J = 3.94, 7.81,11.67 Hz, 1H), 1.88-2.05 (m, 3H), 1.47 (d, J = 7.01 Hz, 3H), 1.14 (d, J= 5.97 Hz, 3H), 1.02 (d, J = 6.10 Hz, 3H). LCMS-ESI (pos.) m/z: 533.2(M + H)⁺. 84.0 (2S,3R)-3-(5-fluoropyrimidin-2- yl)butane-2-sulfonamide(Example 27.1), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and cyclobutanecarbohydrazide (commercially available fromChemBridge Corporation).

(2S,3R)-N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide. ¹H NMR (500 MHz, CDCl₃) δ 10.73 (br s,1H), 8.49- 8.57 (m, 3H), 3.99 (s, 3H), 3.98 (s, 3H), 3.74-3.87 (m, 2H),3.09 (quin, J = 8.40 Hz, 1H), 2.30-2.40 (m, 2H), 2.07-2.13 (m, 2H),1.85-2.04 (m, 2H), 1.39 (d, J = 7.01 Hz, 3H), 1.35 (d, J = 6.88 Hz, 3H).LCMS-ESI (pos.) m/z: 493.2 (M + H)⁺. 85.0(2S,3R)-3-(5-chloropyrimidin-2- yl)butane-2-sulfonamide (Example 27.4),5- isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1), andcyclobutanecarbohydrazide (commercially available from ChemBridgeCorporation).

(2S,3R)-3-(5-chloro-2-pyrimidinyl)-N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide. ¹H NMR (500 MHz, CDCl₃) δ 10.73 (br s, 1H), 8.64(s, 2H), 8.50 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H), 3.85 (quin, J = 6.78Hz, 1H), 3.69-3.79 (m, 1H), 3.09 (quin, J = 8.40 Hz, 1H), 2.30-2.40 (m,2H), 2.06-2.13 (m, 2H), 1.89- 2.04 (m, 2H), 1.38 (d, J = 7.14 Hz, 3H),1.35 (d, J = 7.01 Hz, 3H). LCMS-ESI (pos.) m/z: 509.0 (M + H)⁺. 86.0(1S,2S)-1-isopropoxy-1-(5- methylpyrazin-2-yl)propane-2- sulfonamide(Example 31.2), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and cyclobutanecarbohydrazide (commercially available fromChemBridge Corporation).

(1S,2S)-N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrazinyl)-1-(2-propanyloxy)-2-propanesulfonamide. ¹H NMR (500 MHz,CDCl₃) δ 11.10 (br s, 1H), 8.60 (s, 1H), 8.50 (s, 1H), 8.43 (s, 1H),4.97 (d, J = 5.19 Hz, 1H), 3.95-4.04 (m, 6H), 3.52-3.66 (m, 2H),3.01-3.10 (m, 1H), 2.58-2.63 (m, 3H), 2.26-2.38 (m, 2H), 2.06 (s, 2H),1.89-2.03 (m, 2H), 1.24 (d, J = 7.14 Hz, 3H), 1.17 (d, J = 5.97 Hz, 3H),1.03 (d, J = 6.10 Hz, 3H). LCMS- ESI (pos.) m/z: 533.2 (M + H)⁺. 87.0(2S,3R)-3-(5-chloropyridin-2- yl)butane-2-sulfonamide (Example 32.0), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1), andcyclobutanecarbohydrazide (commercially available from ChemBridgeCorporation).

(2S,3R)-3-(5-chloro-2-pyridinyl)-N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide. ¹H NMR (500 MHz, CDCl₃) δ 10.70 (br s, 1H), 8.48-8.52 (m, 2H), 7.60 (dd, J = 2.40, 8.37 Hz, 1H), 7.17 (d, J = 8.30 Hz,1H), 3.97 (s, 3H), 3.97 (s, 3H), 3.72 (dd, J = 4.35, 7.07 Hz, 1H), 3.61(br dd, J = 4.41, 6.88 Hz, 1H), 3.08 (quin, J = 8.40 Hz, 1H), 2.28-2.40(m, 2H), 1.90-2.13 (m, 4H), 1.36 (d, J = 7.14 Hz, 3H), 1.31 (d, J = 7.01Hz, 3H). LCMS-ESI (pos.) m/z: 508.0 (M + H)⁺. 88.0(2S,3R)-3-(5-methylpyrazin-2- yl)butane-2-sulfonamide (Example 27.2), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1), andcyclobutanecarbohydrazide (commercially available from ChemBridgeCorporation).

(2S,3R)-N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrazinyl)-2-butanesulfonamide. ¹H NMR (500 MHz, CDCl₃) δ 10.72 (br s,1H), 8.49 (s, 1H), 8.36 (d, J = 3.63 Hz, 2H), 3.93-4.00 (m, 6H), 3.70-3.78 (m, 1H), 3.51-3.58 (m, 1H), 3.07 (quin, J = 8.37 Hz, 1H), 2.53 (s,3H), 2.28-2.44 (m, 2H), 1.87-2.10 (m, 4H), 1.37 (d, J = 7.14 Hz, 3H),1.32 (d, J = 7.01 Hz, 3H). LCMS-ESI (pos.) m/z: 489.1 (M + H)⁺. 89.0(1S,2S)-1-(5-chloropyrimidin-2- yl)-1-isopropoxypropane-2- sulfonamide(Example 31.1), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and cyclobutanecarbohydrazide (commercially available fromChemBridge Corporation).

(1S,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-cyclobutyl-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-(2-propanyloxy)-2-propanesulfonamide. ¹H NMR (500 MHz, CDCl₃) δ 11.59(br s, 1H), 8.76 (s, 2H), 8.50(s, 1H), 4.92 (d, J = 4.28 Hz, 1H),3.95-4.05 (m, 6H), 3.75 (dq, J = 4.41, 6.96 Hz, 1H), 3.61 (spt, J = 6.06Hz, 1H), 3.08 (quin, J = 8.24 Hz, 1H), 2.34-2.44 (m, 1H), 2.20-2.32 (m,1H), 2.04-2.18 (m, 2H), 1.87- 2.02 (m, 2H), 1.43 (d, J = 7.01 Hz, 3H),1.15 (d, J = 6.10 Hz, 3H), 1.02 (d, J = 6.10 Hz, 3H). LCMS-ESI (pos.)m/z: 553.1 (M + H)⁺. 90.0 (1R,2S)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2- sulfonamide (Example 29.0), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1), andcyclobutanecarbohydrazide (commercially available from ChemBridgeCorporation).

(1R,2S)-N-(5-cyclobutyl-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide. ¹H NMR (500 MHz, CDCl₃) δ12.90 (br s, 1H), 8.58- 8.73 (m, 3H), 4.73-4.85 (m, 1H), 4.07 (br d, J =4.67 Hz, 1H), 3.94 (s, 3H), 3.93 (br s, 3H), 3.35-3.41 (m, 1H), 3.13 (s,3H), 2.26 (s, 3H), 2.10-2.23 (m, 2H), 2.01 (br d, J = 8.17 Hz, 2H),1.85-1.98 (m, 1H), 1.80 (br s, 1H), 1.11 (br d, J = 6.88 Hz, 3H).LCMS-ESI (pos.) m/z: 505.2 (M + H)⁺. 91.0(1R,2S)-1-(5-chloropyridin-2-yl)- 1-methoxypropane-2-sulfonamide or(1S,2R)-1-(5-chloropyridin-2- yl)-1-methoxypropane-2- sulfonamide(Example 116.0), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and cyclobutanecarbohydrazide (commercially available fromChemBridge Corporation).

(1R,2S)-1-(5-chloropyridin-2-yl)-N-(5-cyclobutyl-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1S,2R)-1-(5-chloropyridin-2-yl)-N-(5-cyclobutyl-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 12.96 (s, 1H),8.67 (s, 1H), 8.60 (d, J = 2.08 Hz, 1H), 7.95 (dd, J = 2.27, 8.37 Hz,1H), 7.39 (br d, J = 8.43 Hz, 1H), 4.84 (s, 1H), 3.93 (s, 3H), 3.92 (brs, 3H), 3.17-3.23 (m, 2H), 3.15 (s, 3H), 2.10-2.24 (m, 2H), 2.02 (br d,J = 8.30 Hz, 2H), 1.87-1.99 (m, 1H), 1.75-1.86 (m, 1H), 0.97 (br d, J =7.01 Hz, 3H). LCMS-ESI (pos.) m/z: 524.2 (M + H)⁺. 92.0(2S,3R)-3-(5-methoxypyrimidin- 2-yl)butane-2-sulfonamide (Example 27.6),5- isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1), andcyclobutanecarbohydrazide (commercially available from ChemBridgeCorporation).

(1R,2S)-N-(5-cyclobutyl-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methoxypyrimidin-2-yl)propane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ12.93 (br s, 1H), 8.67 (s, 1H), 8.48 (s, 2H), 3.91 (m, 6H), 3.88 (s,3H), 3.64 (br d, J = 4.15 Hz, 2H), 3.51-3.56 (m, 1H), 2.12- 2.22 (m,2H), 2.02 (br s, 2H), 1.88-1.98 (m, 1H), 1.81 (br s, 1H), 1.22 (br d, J= 7.14 Hz, 3H), 1.07 (br d, J = 6.88 Hz, 3H). LCMS-ESI (pos.) m/z: 505.2(M + H)⁺. 93.0 (1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2-sulfonamide (Example 29.3), 2- isothiocyanato-1,3- dimethoxybenzene(Example 28.0), and cyclobutanecarbohydrazide (commercially availablefrom ChemBridge Corporation).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, CDCl₃) δ 10.70 (br s,1H), 8.71 (s, 2H), 7.40 (t, J = 8.36 Hz, 1H), 6.63 (d, J = 8.56 Hz, 2H),4.94 (d, J = 5.06 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.64-3.75 (m,1H), 3.34 (s, 3H), 3.08 (quin, J = 8.34 Hz, 1H), 2.28-2.37 (m, 2H),1.85-2.06 (m, 4H), 1.37 (d, J = 7.01 Hz, 3H). LCMS-ESI (pos.) m/z: 523.2(M + H)⁺. 94.0 (1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2-sulfonamide (Example 29.3), 1,3- difluoro-2-isothiocyanatobenzene(commercially available from Sigma Aldrich), andcyclobutanecarbohydrazide (commercially available from ChemBridgeCorporation).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-cyclobutyl-4-(2,6-difluorophenyl)-4H-1,24-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, CDCl₃) δ 10.75 (br s,1H), 8.73 (s, 2H), 7.48-7.56 (m, 1H), 7.06-7.15 (m, 2H), 4.97 (d, J =4.54 Hz, 1H), 3.68-3.76 (m, 1H), 3.35 (s, 3H), 3.20 (quin, J = 8.40 Hz,1H), 2.32-2.42 (m, 2H), 2.05-2.15 (m, 2H), 1.91-2.03 (m, 2H), 1.37 (d, J= 7.01 Hz, 3H). LCMS-ESI (pos.) m/z: 499.0 (M + H)⁺. 95.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 2- isothiocyanato-1,3- dimethoxypropane (Example 113.0),and cyclobutanecarbohydrazide (commercially available from ChemBridgeCorporation).

  (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-cyclobutyl-4-(1,3-dimethoxypropan-2-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, CDCl₃) δ 10.71 (br s,1H), 8.74 (s, 2H), 5.03 (d, J = 4.28 Hz, 1H), 4.01-4.19 (m, 3H), 3.61-3.74 (m, 3H), 3.45-3.55 (m, 1H), 3.36 (s, 3H), 3.33 (s, 3H), 3.32 (s,3H), 2.33-2.46 (m, 4H), 1.92-2.03 (m, 1H), 1.41 (d, J = 7.01 Hz, 3H).LCMS-ESI (pos.) m/z: 489.2 (M + H)⁺. 96.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 1- isothiocyanato-1- (methoxymethyl)cyclopropane(Example 114.0), and cyclobutanecarbohydrazide (commercially availablefrom ChemBridge Corporation).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-cyclobutyl-4-(1-(methoxymethypcyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, CDCl₃) δ 10.64 (brs, 1H), 8.74 (s, 2H), 5.09 (d, J = 3.76 Hz, 1H), 3.86 (quin, J = 8.56Hz, 1H), 3.62-3.80 (m, 1H), 3.30 (m, 6H), 2.34 (br s, 3H), 1.69-2.21 (m,3H), 1.42 (d, J = 7.14 Hz, 3H), 1.14 (m, 6H). LCMS-ESI (pos.) m/z: 471.2(M + H)⁺. 97.0 (1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2-sulfonamide (Example 29.3), 4- isothiocyanatotetrahydro-2H- pyran(commercially available from Oakwood Products, Inc.), andcyclobutanecarbohydrazide (commercially available from ChemBridgeCorporation).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-cyclobutyl-4-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, CDCl₃) δ 10.76 (br s,1H), 8.74 (s, 2H), 5.12 (d, J = 3.50 Hz, 1H), 4.09-4.20 (m, 4H), 3.66-3.75 (m, 1H), 3.44 (dt, J = 3.50, 11.68 Hz, 2H), 3.36 (s, 3H), 2.54-2.64(m, 2H), 2.37-2.48 (m, 4H), 2.09-2.20 (m, 1H), 1.98-2.05 (m, 1H), 1.69(br d, J = 10.12 Hz, 2H), 1.40 (d, J = 7.14 Hz, 3H). LCMS-ESI (pos.)m/z: 471.2 (M + H)⁺.

Example 113.0. Preparation of 2-isothiocyanato-1,3-dimethoxypropane

2-Isothiocyanato-1,3-dimethoxypropane, Example 113.0

To a dry 200 round-bottom flask was added di(2-pyridyl) thionocarbonate(5.34 g, 23.00 mmol) in DCM (73.0 mL). 2-Amino-1,3-dimethoxypropane inDCM (15 mL) was added dropwise via an addition funnel over 5 mins. Thereaction mixture was then stirred at RT for 3.5 h. The reaction mixturewas concentrated in vacuo. The material was absorbed onto a plug ofsilica gel and purified by chromatography through a Redi-Sep pre-packedsilica gel column (40 g), eluting with a gradient of 0% to 50% EtOAc inheptanes, to provide 2-isothiocyanato-1,3-dimethoxypropane (3.28 g,20.34 mmol, 93% yield) as a colorless oil. LCMS-ESI (pos.) m/z: 162.2(M+H)⁺.

The compound set forth in the following table was synthesized followingthe procedure in Example 113.0 using the known starting material asdescribed.

TABLE 13 Example Reagents Structure, Name and Data 114.01-(methoxymethyl)cyclopropanamine hydrochloride (commercially availablefrom J & W Pharm Lab), and N,N- diisopropylethylamine (commerciallyavailable from Signa Aldrich).

The compounds set forth in the following table were synthesizedfollowing the procedure in Example 42.0 using the known startingmaterial as described.

TABLE 14 Example Reagents Structure, Name and Data 118.0(1R,2S)-1-(5-chloropyrimidin-2-yl)-1- methoxypropane-2-sulfonamide(Example 29.3), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 3- methylenecyclobutanecarbohydrazide (commercially availablefrom Focus Synthesis).

119.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1- methoxypropane-2-sulfonamide(Example 29.3), 2-isothiocyanato-1,3- dimethoxybenzene (Example 28.0),and 3,3- dimethylcyclobutanecarbohydrazide (material prepared in ananalogous manner to that of Example 42.2 employing methyl 3,3-dimethylcyclobutanecarboxylate (commercially available from AdvancedChemblocks Inc.)).

120.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1- methoxypropane-2-sulfonamide(Example 29.3), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 3,3- dimethylcyclobutanecarbohydrazide (material prepared inan analogous manner to that of Example 42.2 employing methyl 3,3-dimethylcyclobutanecarboxylate (commercially available from AdvancedChemblocks Inc)).

121.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1- methoxypropane-2-sulfonamide(Example 29.3), 2-isothiocyanato-1,3- dimethoxybenzene (Example 28.0),and 3-cyanocyclobutanecarbohydrazide (material prepared in an analogousmanner to that of Example 42.2 employing methyl 3-cyanocyclobutanecarboxylate (commercially available from AstaTech,Inc.)). Methansulfonic acid was used instead of sodium hydroxide. Themixture was purified by preparative SFC method using the followingmethodology: Column: Chiralpak AS-H 2 × 25 cm, Mobile Phase: 25% MeOH,Flow Rate: 80 mL/min, 215 nm, Volume: 0.50 mL of a 14.5 mg/mL solutionin MeOH to deliver Peak 1.

 

(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(cis-3-cyanocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide or(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(trans-3-cyanocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide ¹H NMR (500 MHz,CDCl₃) δ 10.80 (br. s, 1H), 8.72 (s, 2H), 7.42 (t, J = 8.35 Hz, 1H),6.65 (dd, J = 1.17, 8.56 Hz, 2H), 4.94 (d, J = 4.93 Hz, 1H), 3.81 (s,3H), 3.80 (s, 3H), 3.66-3.76 (m, 1H), 3.34 (s, 3H), 3.06- 3.17 (m, 1H),3.01 (quin, J = 9.21 Hz, 1H), 2.70-2.77 (m, 2H), 2.40-2.48 (m, 2H), 1.36(d, J = 7.01 Hz, 3H). LCMS-ESI (pos.) m/z: 548.2 (M + H)⁺. 122.0(1R,2S)-1-(5-chloropyrimidin-2-yl)-1- methoxypropane-2-sulfonamide(Example 29.3), 2-isothiocyanato-1,3- dimethoxybenzene (Example 28.0),and 3-cyanocyclobutanecarbohydrazide (material prepared in an analogousmanner to that of Example 42.2 employing methyl 3-cyanocyclobutanecarboxylate (commercially available from AstaTech,Inc.)). Methanesulfonic acid was used instead of sodium hydroxide. Themixture was purified by preparative SFC method using the followingmethodology: Column: Chiralpak AS-H 2 × 25 cm, Mobile Phase: 25% MeOH,Flow Rate: 80 mL/min, 215 nm, Volumn: 0.50 mL of a 14.5 mg/mL solutionin MeOH to deliver Peak 1.

 

(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(cis-3-cyanocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide or(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(trans-3-cyanocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide. ¹H NMR (500 MHz,CDCl3) δ 10.34-11.23 (m, 1H), 8.72 (s, 2H), 7.43 (t, J = 8.50 Hz, 1H),6.66 (dd, J = 1.95, 8.56 Hz, 2H), 4.94 (d, J = 4.93 Hz, 1H), 3.81 (s,3H), 3.80 (s, 3H), 3.65-3.75 (m, 1H), 3.34-3.37 (m, 1H), 3.33 (s, 3H),3.19-3.26 (m, 1H), 2.72-2.79 (m, 2H), 2.44-2.52 (m, 2H), 1.36 (d, J =7.01 Hz, 3H). LCMS-ESI (pos.) m/z: 548.2 (M + H)⁺. 123.0(1R,2S)-1-(5-chloropyrimidin-2-yl)-1- methoxypropane-2-sulfonamide(Example 29.3), 2-isothiocyanato-1,3- dimethoxybenzene (Example 28.0),and 3- hydroxycyclobutanecarbohydrazide (material prepared in ananalogous manner to that of Example 42.2 employing ethyl 3-hydroxycyclobutanecarboxylate (commercially available from Synthonix)).The mixture was purified by preparative SFC method using the followingmethodology: Column: Chiralpak AS-H 2 × 25 cm, Mobile Phase: 25% MeOH,Flow Rate: 80 mL/min, 215 nm, Volume: 1 mL of a 10 mg/mL solution inMeOH to deliver Peak 1.

 

(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6- dimethoxyphenyl)-5-(cis-3-(hydroxymethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide or (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(trans-3-(hydroxymethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide. ¹H NMR (500 MHz, CDCl₃) δ8.71 (s, 2H), 7.40 (t, J = 8.43 Hz, 1H), 6.64 (d, J = 8.56 Hz, 2H), 5.31(s, 1H), 4.94 (d, J = 4.93 Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H),3.63-3.75 (m, 1H), 3.58 (d, J = 6.10 Hz, 2H), 3.34 (s, 3H), 2.98 (quin,J = 8.86 Hz, 1H), 2.38-2.48 (m, 1H), 2.05-2.18 (m, 4H), 1.36 (d, J =6.88 Hz, 3H). LCMS-ESI (pos.) m/z: 553.0 (M + H)⁺. 124.0(1R,2S)-1-(5-chloropyrimidin-2-yl)-1- methoxypropane-2-sulfonamide(Example 29.3), 2-isothiocyanato-1,3- dimethoxybenzene (Example 28.0),and 3-hydroxycyclobutane- carbohydrazide (material prepared in ananalogous manner to that of Example 42.2 employing ethyl 3-hydroxycyclobutanecarboxylate (commercially available from Synthonix)).The mixture was purified by preparative SFC method using the followingmethodology: Column: Chiralpak AS-H 2 × 25 cm, Mobile Phase: 25% MeOH,Flow Rate: 80 mL/min, 215 nm, Volume: 1 mL of a 10 mg/mL solution inMeOH to deliver Peak 2.

 

(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6- dimethoxyphenyl)-5-(cis-3-(hydroxymethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide or (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(trans-3-(hydroxymethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide. ¹H NMR (500 MHz, CDCl₃) δ8.71 (s, 2H), 7.40 (t, J = 8.43 Hz, 1H), 6.63 (br d, J = 8.04 Hz, 2H),4.94 (d, J = 4.93 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.69 (br dd, J =5.19, 6.75 Hz, 1H), 3.63 (d, J = 6.62 Hz, 2H), 3.34 (s, 3H), 3.07 (quin,J = 7.98 Hz, 1H), 2.49-2.62 (m, 1H), 2.38-2.48 (m, 2H), 1.83-2.01 (m,3H), 1.36 (d, J = 6.88 Hz, 3H). LCMS-ESI (pos.) m/z: 553.2 (M + H)⁺.125.0 1-(pyridin-2- yl)cyclopropanecarbohydrazide (Example 42.4),2-isothiocyanato-1,3- dimethoxybenzene (Example 28.0), and(2S,3R)-3-(5-chloropyrimidin-2- yl)butane-2-sulfonamide (Example 27.4).

126.0 1-(pyridin-2- yl)cyclopropanecarbohydrazide (Example 42.4),2-isothiocyanato-1,3- dimethoxybenzene (Example 28.0), and(2S,3R)-3-(5-methylpyrimidin-2- yl)butane-2-sulfonamide (Example 27.0).

127.0 1-(pyridin-2- yl)cyclobutanecarbohydrazide (Example 42.5),2-isothiocyanato-1,3- dimethoxybenzene (Example 28.0), and(2S,3R)-3-(5-methylpyrimidin-2- yl)butane-2-sulfonamide (Example 27.0).

128.0 cyclobutanecarbohydrazide (commercially available from ChemBridgeCorporation), 2- isothiocyanatopropane (commercially available fromSigma Aldrich), and (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2-sulfonamide (Example 29.3).

129.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2-sulfonamide, (Example 29.3), 2-isothiocyanato-1,3-dimethoxybenzene (Example 28.0), and 3- hydroxycyclobutanecarbohydrazide(material prepared in an analogous manner to that of Example 42.2employing ethyl 3- hydroxycyclobutanecarboxylate (commercially availablefrom Synthonix)).

 

(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(cis-3-(hydroxymethyl)cyclobutyl)-4-(1-(methoxymethyl)cyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide and (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(trans-3- (hydroxymethyl)cyclobutyl)-4-(1-(methoxymethyl)cyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide. ¹H NMR (500 MHz, CDCl₃) δ 8.72 (s,2H), 5.02- 5.14 (m, 1H), 3.66 (s, 5H), 3.28 (m, 6H), 2.51-2.72 (m, 2H),2.37-2.51 (m, 2H), 2.23 (br d, J = 5.45 Hz, 2H), 1.41 (d, J = 7.01 Hz,3H), 1.26 (br t, J = 7.14 Hz, 2H), 1.13 (br d, J = 10.12 Hz, 2H).LCMS-ESI (pos.) m/z: 501.0 (M + H)⁺. 130.03-hydroxycyclobutanecarbohydrazide (material prepared in an analogousmanner to that of Example 42.2 employing ethyl 3-hydroxycyclobutanecarboxylate commercially available from Synthonix),2-isothiocyanato-1,3- dimethoxypropane (Example 113.0), and(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2-sulfonamide(Example 29.3). The mixture was separated by SFC using Phenomenex LuxCellulose-2, 35% iPrOH. This was the first isomer to elute under theseconditions.

 

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(1,3-dimethoxypropan-2-yl)-5-((1r,3S)-3-(hydroxymethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(1,3-dimethoxypropan-2-yl)-5-((1s,3R)-3-(hydroxymethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz,CDCl₃) δ 8.65-8.77 (m, 2 H) 4.99-5.07 (m, 1 H) 4.11-4.25 (m, 1 H)4.00-4.10 (m, 2 H) 3.67-3.72 (m 1 H) 3.61-3.65 (m 3 H) 3.38-3.45 (m, 1H) 3.29-3.36 (m, 9 H) 2.55-2.64 (m 1 H) 2.40-2.48 (m, 2 H) 2.19-2.30 (m,2 H) 1.34-1.47 (m, 3 H) 1.24-1.33 (m, 1 H). LCMS- ESI (pos.) m/z: 519.0(M + H)⁺. 131.0 3-hydroxycyclobutanehydrazide (material prepared in ananalogous manner to that of Example 42.2 employing ethyl 3-hydroxycyclobutanecarboxylate (commercially available from Synthonix),2-isothiocyanato-1,3- dimethoxypropane (Example 113.0), and(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2-sulfonamide(Example 29.3). The mixture was separated by SFC using Phenomenex LuxCellulose-2, 35% iPrOH. This was the second isomer to elute under theseconditions.

 

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(1,3-dimethoxypropan-2-yl)-5-((1r,3S)-3-(hydroxymethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(1,3-dimethoxypropan-2-yl)-5-((1s,3R)-3-(hydroxymethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz,CDCl₃) δ 8.65-8.80 (m, 2H) 5.00-5.07 (m, 1 H) 4.03-4.18 (m, 3 H)3.73-3.77 (m 2 H) 3.68-3.73 (m, 1 H) 3.58-3.66 (m, 2 H) 3.47-3.55 (m, 1H) 3.28-3.39 (m, 9 H) 2.58-2.66 (m, 1 H) 2.49-2.57 (m, 2 H) 2.20-2.27(m, 2 H) 1.38-1.43 (m, 3 H). LCMS-ESI (pos.) m/z: 519.0 (M + H)⁺.

The compounds set forth in the following table were synthesizedfollowing the procedure in Example 42.0 using the known startingmaterial as described.

TABLE 15 Example Reagents Structure, Name and Data 145.14-(difluoromethyl)cyclohexane-1- carboxylic acid (commercially availablefrom Enamine).

146.1 2-(difluoromethyl)cyclobutanecarboxylic acid (commerciallyavailable from Enamine).

147.1 3,3-difluorocyclobutane-1-carboxylic acid (commercially availablefrom Synthonix).

148.1 3-methylcyclobutane-1-carboxylic acid (commercially available fromSynthonix).

149.1 3-(trifluoromethyl)cyclobutane-1- carboxylic acid (commerciallyavailable from Synthonix).

151.1 3-fluorocyclobutane-1-carboxylic acid (commercially available fromSynthonix).

153.1 3-chlorocyclobutane-1-carboxylic acid (commercially available fromSynthonix).

154.1 3-methoxycyclobutane-1-carboxylic acid (commercially availablefrom Synthonix).

159.1 2,2-difluorocyclobutane-1-carboxylic acid (commercially availablefrom Enamine).

169.1 2-cyanocyclobutane-1-carboxylic acid (commercially available fromEnamine).

179.1 2-fluorocyclobutane-1-carboxylic acid (commercially available fromEnamine).

188.1 2-methylcyclobutane-1-carboxylic acid (commercially available fromEnamine).

200.1 spiro[2.3]hexane-5-carboxylic acid (commercially available fromEnamine)

175.1 4-fluorocyclohexane-1-carboxylic acid (commercially available fromEnamine)

238.1 3,3-dimethoxycyclobutane-1-carboxylic acid (commercially availablefrom Frontier Scientific Services Inc.).

The compounds set forth in the following table were synthesizedfollowing the procedure in Example 42.0 using the known startingmaterial as described.

TABLE 16 Example Reagents Structure, Name and Data 132.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5-1- isothiocyanato-1- (methoxymethyl)cyclopropane(Example 114.0), and 3- hydroxycyclobutanecarbohydrazide (material wasprepared in an analogous manner to that of Example 42.2 employing ethyl3- hydroxycyclobutanecarboxylate (commercially available fromSynthonix)).

 

(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(trans-3-(hydroxymethyl)cyclobutyl)-4-(1-(methoxymethyl)cyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide or (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(cis-3-(hydroxymethyl)cyclobutyl)-4-(1-(methoxymethyl)cyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide. ¹H NMR (500 MHz, DMSO-d6) δ 12.34-12.74(m, 1 H) 8.85-9.03 (m, 2 H) 4.89-4.96 (m, 1 H) 4.59-4.66 (m, 1 H)4.02-4.12 (m, 1 H) 3.46-3.52 (m, 2 H) 3.38-3.46 (m, 2 H) 3.29 (s, 1 H)3.21 (s, 3 H) 3.15-3.18 (m, 3 H) 3.05-3.12 (m, 3 H) 2.37-2.41 (m, 1 H)2.07-2.17 (m, 2 H) 1.25 (d, J = 7.0 Hz, 3 H) 1.07-1.11 (m, 1 H)1.06-1.11 (m, 1 H). LCMS-ESI (pos.) m/z: 501.2 (M + H)⁺. 133.01R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5-1- isothiocyanato-1- (methoxymethyl)cyclopropane(Example 114.0), and 3- hydroxycyclobutanecarbohydrazide (material wasprepared in an analogous manner to that of Example 42.2 employing ethyl3- hydroxycyclobutanecarboxylate (commercially availabe fromSynthonix)).

 

(1R,2S)-1-(5-chloro-2-pyriminidyl)-N-(5-(trans-3-(hydroxymethyl)cyclobutyl)-4-(1-(methoxymethyl)cyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide or (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(cis-3-(hydroxymethyl)cyclobutyl)-4-(1-(methoxymethyl)cyclopropyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 12.39-12.62(m, 1 H) 8.86-9.02 (m, 2 H) 4.87-4.99 (m, 1 H) 4.43-4.54 (m, 1 H)4.02-4.21 (m, 1 H) 3.58-3.66 (m, 1 H) 3.39-3.46 (m, 1 H) 3.35 (t, J =5.6 Hz, 2 H) 3.29-3.29 (m, 1 H) 3.22 (s, 3 H) 3.15-3.18 (m, 3 H)3.04-3.12 (m, 3 H) 2.35- 2.42 (m, 1 H) 2.25-2.34 (m, 1 H) 1.23-1.27 (m,3 H) 1.04-1.16 (m, 3 H). LCMS-ESI (pos.) m/z: 501.2 (M + H)⁺. 134.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5-1- isothiocyanatocyclopropane (commercially availablefrom Sigma-Aldrich), and 3- hydroxycyclobutanecarbohydrazide (materialwas prepared in an analogous manner to that of Example 42.2 employingethyl 3- hydroxycyclobutanecarboxylate (commercially available fromSynthonix)).

 

(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-cyclopropyl-5-(trans-3-(hydroxymethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide or (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-cyclopropyl-5-(cis-3-(hydroxymethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide. ¹H NMR (500 MHz, CDCl₃) δ 10.22-11.14 (m,1 H) 8.63- 8.84 (m, 2 H) 4.99-5.11 (m, 1 H) 3.76-3.81 (m, 2 H) 3.68-3.75(m, 1 H) 3.60-3.68 (m, 1 H) 3.32 (s, 3 H) 2.73 (br s, 2 H) 2.43-2.55 (m,2 H) 2.26-2.39 (m, 2 H) 1.42- 1.46 (m, 3 H) 0.99-1.17 (m, 4 H). LCMS-ESI(pos.) m/z: 457.2 (M + H)⁺. 135.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2- sulfonamide (Example 29.3), 5-1-isothiocyanatocyclopropane (commercially available from Sigma-Aldrich),and 3- hydroxycyclobutanecarbohydrazide (material was prepared in ananalogous manner to that of (Example 42.2) employing ethyl3-hydroxycyclobutanecarboxylate (commercially available fromSynthonix)).

 

(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-cyclopropyl-5-(trans-3-(hydroxymethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide or (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-cyclopropyl-5-(cis-3-(hydroxymethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide. ¹H NMR (500 MHz, CDCl₃) δ 10.44-10.84 (m,1 H) 8.61- 8.79 (m, 2 H) 4.92-5.17 (m, 1 H) 3.62-3.76 (m, 3 H) 3.51-3.57(m, 1 H) 3.32 (s, 3 H) 2.59-2.78 (m, 2 H) 2.41- 2.57 (m, 2 H) 2.12-2.31(m, 2 H) 1.43 (br d, J = 6.4 Hz, 3 H) 1.13 (br s, 4 H). LCMS-ESI (pos.)m/z: 457.2 (M + H)⁺. 136.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2- sulfonamide (Example 29.3), 5-1-2-isocyanatopropane (commercially available from Sigma-Aldrich), and 3-(hydroxymethyl)cyclobutane-1- carbohydrazide (material was prepared inan analogous manner to that of Example 42.2 employing ethyl 3-hydroxycyclobutanecarboxylate (commercially available from Synthonix)).

 

(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-trans-3-(hydroxymethyl)cyclobutyl)-4-(2-propanyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide or (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(cis-3-(hydroxymethyl)cyclobutyl)-4-(2-propanyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide. ¹H NMR (500 MHz, CDCl₃) δ10.53-10.88 (m, 1 H) 8.74 (s, 2 H) 5.02-5.12 (m, 1 H) 4.18-4.35 (m, 1 H)3.78 (d, J = 6.1 Hz, 2 H) 3.69-3.75 (m, 1 H) 3.51 (s, 4 H) 3.36 (s, 3 H)2.58-2.71 (m, 1 H) 2.45-2.56 (m, 2 H) 2.24-2.35 (m, 2 H) 1.54-1.56 (m, 3H) 1.42 (d, J = 7.0 Hz, 3 H). LCMS-ESI (pos.) m/z: 459.2 (M + H)⁺. 137.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5-1- 2-isothiocyanatopropane (commercially availablefrom Sigma-Aldrich), and 3- (hydroxymethyl)cyclobutane-1- carbohydrazide(material was prepared in an anlogous manner to that of Example 42.2employing ethyl 3- hydroxycyclobutanecarboxylate (commercially availablefrom Synthonix)).

 

(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(trans-3-(hydroxymethyl)cyclobutyl)-4-(2-propanyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide or (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(cis-3-(hydroxymethyl)cyclobutyl)-4-(2-propanyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide. ¹H NMR (500 MHz, CDCl₃) δ10.49-10.92 (m, 1 H) 8.64- 8.85 (m, 2 H) 4.89-5.17 (m, 1 H) 4.28-4.37(m, 1 H) 3.68-3.75 (m, 1 H) 3.63-3.68 (m, 2 H) 3.50-3.52 (m, 3 H)3.33-3.43 (m, 4 H) 2.60-2.71 (m, 1 H) 2.43-2.53 (m, 2 H) 2.17-2.30 (m, 2H) 1.55-1.57 (m, 3 H) 1.40- 1.44 (m, 3 H) LCMS-ESI (pos.) m/z: 459.2(M + H)⁺. 138.0 (1R,2S)-1-methoxy-1-(5- methylpyrazin-2-yl)propane-2-sulfonamide (Example 29.1), isothiocyanato-1,3- dimethoxybenzene(Example 28.0), home cyclobutanecarbohydrazide (commercially availablefrom ChemBridge Corporation).

139.0 (2S,3R)-3-(5-methylpyrazin-2- yl)butane-2-sulfonamide (Example27.2), isothiocyanato- 1,3-dimethoxybenzene (Example 28.0, andcyclobutanecarbohydrazide (commercially available from ChemBridgeCorporation).

140.0 (1S,2S)-1-isopropoxy-1-(5- methylpyrazin-2-yl)propane-2-sulfonamide (Example 31.02), isothiocyanato-1,3- dimethoxybenzene(Example 28.0), and cyclobutanecarbohydrazide (commercially availablefrom ChemBridge Corporation).

141.0 (1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propane-2-sulfonamide (Example 29.0), isothiocyanato-1,3- dimethoxybenzene(Example 28.0), and cyclobutanecarbohydrazide (commercially availablefrom ChemBridge Corporation).

142.0 (1S,2S)-1-isopropoxy-1-(5- methylpyrimidin-2-yl)propane-2-sulfonamide (Example 31.0), isothiocyanato-1,3- dimethoxybenzene(Example 28.0), and cyclobutanecarbohydrazide (commercially availablefrom ChemBridge Corporation).

143.0 (2S,3R)-3-(5-chloropyrimidin-2- yl)butane-2-sulfonamide (Example27.4), isothiocyanato- 1,3-dimethoxybenzene, (Example 28.0), andcyclobutanecarbohydrazide (commerically available from ChemBridgeCorporation).

144.0 (1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2-sulfonamide (Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine(Example 28.1), and (1s,4s)-4- (difluoromethyl)cyclohexane-1-carbohydrazide and (1r,4r)-4- (difluoromethyl)cyclohexane-1-carbohydrazide (Example 145.1).

(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(cis-4-(difluoromethyl)cyclohexyl)-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2- propanesulfonamide or(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(trans-4-(difluoromethyl)cyclohexyl)-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 12.87-13.06(m, 1 H) 8.93 (s, 2 H) 8.70 (s, 1 H) 5.80 (d, J = 4.2 Hz, 1 H) 4.77 (d,J = 4.0 Hz, 1 H) 3.96 (m, 6 H) 3.34-3.41 (m, 1 H) 3.12 (s, 3 H)2.23-2.32 (m, 1 H) 1.71-1.83 (m, 5 H) 1.39-1.51 (m, 2 H) 1.12 (d, J =7.0 Hz, 5 H). LCMS-ESI (pos.) m/z: 603.0 (M + H)⁺. 145.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and (1s,4s)-4- (difluoromethyl)cyclohexane-1- carbohydrazide and(1r,4r)-4- (difluoromethyl)cyclohexane-1- carbohydrazide (Example145.1).

(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(cis-4-(difluoromethyl)cyclohexyl)-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2- propanesulfonamide or(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-(trans-4-(difluoromethyl)cyclohexyl)-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide. ¹H NMR (500 MHz, DMSO-d6) δ 12.87-13.06(m, 1 H) 8.93 (s, 2 H) 8.70 (s, 1 H) 5.80 (d, J = 4.2 Hz, 1 H) 4.77 (d,J = 4.0 Hz, 1 H) 3.96 (m, 6 H) 3.34-3.41 (m, 1 H) 3.12 (s, 3 H)2.23-2.32 (m, 1 H) 1.71-1.83 (m, 5 H) 1.39-1.51 (m, 2 H) 1.12 (m, 5 H).LCMS-ESI (pos.) m/z: 603.0 (M + H)⁺. 146.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 3-4- (difluoromethyl)cyclohexane-1- carbohydrazide (Example146.1).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1R,2S)-2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide and(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1S,2R)-2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1R,2R)-2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide and(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1S,2S)-2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 12.98-13.14(m, 1 H) 8.91-9.00 (m, 2 H) 8.66-8.74 (m, 1 H) 6.02 (d, J = 4.4 Hz, 1 H)4.72-4.88 (m, 1 H) 3.94 (m, 6 H) 3.39 (br d, J = 7.0 Hz, 1 H) 3.15-3.22(m, 1 H) 3.13 (d, J = 4.4 Hz, 3 H) 3.00-3.11 (m, 1 H) 1.99 (s, 3 H)1.83-1.95 (m, 1 H) 1.13 (d, J = 7.0 Hz, 3 H). LCMS-ESI (pos.) m/z: 575.0(M + H)⁺. 147.0 (1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2-sulfonamide (Example 29.3), isothiocyanato-1,3- dimethoxybenzene(Example 28.0), and 3,3- difluorocyclobutane-1- carbohydrazide (Example147.1).

148.0 (1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2-sulfonamide (Example 29.3), isothiocyanato-1,3- dimethoxybenzene(Example 28.0), and (1s,3s)-3- methylcyclobutane-1- carbohydrazide and(1r,3r)-3- methylcyclobutane-1- carbohydrazide (Example 148.1).

 

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1r,3S)-3-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide and(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1r,3R)-3-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz,DMSO-d₆) δ 12.57-12.75 (m, 1 H) 8.82-8.96 (m, 2 H) 7.34-7.60 (m, 1 H)6.83 (br d, J = 8.4 Hz, 2 H) 4.70-4.79 (m, 1 H) 3.72-3.75 (m, 6 H) 3.35-3.43 (m, 1 H) 3.11-3.18 (m, 3 H) 2.73-3.05 (m, 1 H) 2.18-2.42 (m, 2 H)2.00-2.12 (m, 1 H) 1.68-1.78 (m, 1 H) 1.58-1.68 (m, 1 H) 1.13 (d, J =6.9 Hz, 3 H) 0.90-1.04 (m, 3 H). LCMS-ESI (pos.) m/z: 537.2 (M + H)⁺.149.0 (1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2-sulfonamide (Example 29.3), isothiocyanato-1,3- dimethoxybenzene(Example 28.0), and (1s,3s)-3- (trifluoromethyl)cyclobutane-1-carbohydrazide and (1r,3r)-3- (trifluoromethyl)cyclobutane-1-carbohydrazide (Example 149.1).

 

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1r,3S)-3-(trifluoromethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1s,3R)-3-(trifluoromethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ12.74-13.06 (m, 1 H) 8.73-9.05 (m, 2 H) 7.51 (t, J = 8.5 Hz, 1 H) 6.85(dd, J = 8.6, 1.4 Hz, 2 H) 4.62-4.79 (m, 1 H) 3.74-3.77 (m, 6 H)3.36-3.43 (m, 1 H) 3.01-3.22 (m, 5 H) 2.07-2.32 (m, 4 H) 1.00-1.24 (m, 3H). LCMS-ESI (pos.) m/z: 591.0 (M + H)⁺. 150.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), isothiocyanato-1,3- dimethoxybenzene (Example 28.0), and(1s,3s)-3- (trifluoromethyl)cyclobutane-1- carbohydrazide and (1r,3r)-3-(trifluoromethyl)cyclobutane-1- carbohydrazide (Example 149.1).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1r,3S)-3-(trifluoromethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1s,3R)-3-(trifluoromethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ12.81-12.96 (m, 1 H) 8.71-9.05 (m, 2 H) 7.51 (t, J = 8.5 Hz, 1 H)6.74-6.95 (m, 2 H) 4.68-4.81 (m, 1 H) 3.70-3.81 (m, 6 H) 3.46-3.54 (m, 4H) 3.02-3.24 (m, 6 H) 2.11-2.22 (m, 2 H) 1.11- 1.17 (m, 3 H). LCMS-ESI(pos.) m/z: 591.0 (M + H)⁺. 151.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2- sulfonamide (Example 29.3), isothiocyanato-1,3-dimethoxybenzene (Example 28.0), and (1s,3s)-3- fluorocyclobutane-1-carbohydrazide and (1r,3r)-3- fluorocyclobutane-1- carbohydrazide(Example 151.1).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1r,3S)-3-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1r,3R)-3-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz,DMSO-d₆) δ 1.09-1.16 (m, 3 H) 3.01-3.09 (m, 1 H) 3.11-3.16 (m, 3 H)3.35-3.42 (m, 1 H) 3.71-3.79 (m, 7 H) 4.73-4.81 (m, 1 H) 5.03-5.25 (m, 1H) 6.79-6.90 (m, 2 H) 7.46-7.52 (m, 1 H) 8.90- 8.96 (m, 2 H) 12.78-12.87(m 1 H). LCMS-ESI (pos.) m/z: 541.0 (M + H)⁺. 152.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), isothiocyanato-1,3- dimethoxybenzene (Example 28.0), and(1s,3s)-3- fluorocyclobutane-1- carbohydrazide and (1r,3r)-3-fluorocyclobutane-1- carbohydrazide (Example 151.1).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1r,3S)-3-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1s,3R)-3-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz,DMSO-d6) δ 12.79-12.88 (m, 1 H) 8.84-8.98 (m, 2 H) 7.44-7.58 (m, 1 H)6.84 (dd, J = 8.6, 1.2 Hz, 2 H) 4.83-5.05 (m, 1 H) 4.76 (d, J = 4.3 Hz,1 H) 3.74-3.76 (m, 6 H) 3.36-3.46 (m, 1 H) 3.14 (s, 3 H) 2.53- 2.58 (m,1 H) 2.39-2.44 (m, 2 H) 2.21-2.33 (m, 2 H) 1.13 (d, J = 7.0 Hz, 3 H).LCMS-ESI (pos.) m/z: 541.0 (M + H)⁺. 153.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), isothiocyanato-1,3- dimethoxybenzene (Example 28.0), and(1s,3s)-3- chlorocyclobutane-1- carbohydrazide and (1r,3r)-3-chlorocyclobutane-1- carbohydrazide (Example 153.1).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1r,3S)-3-chlorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1s,3R)-3-chlorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz,DMSO-d₆) δ 12.79-12.88 (m, 1 H) 8.84-8.98 (m, 2 H) 7.44-7.58 (m, 1 H)6.84 (dd, J = 8.6, 1.2 Hz, 2 H) 4.83-5.05 (m, 1 H) 4.76 (d, J = 4.3 Hz,1 H) 3.74-3.76 (m, 6 H) 3.36-3.46 (m, 1 H) 3.14 (s, 3 H) 2.53- 2.58 (m,1 H) 2.39-2.44 (m, 2 H) 2.21-2.33 (m, 2 H) 1.13 (d, J = 7.0 Hz, 3 H).LCMS-ESI (pos.) m/z: 541.0 (M + H)⁺. 154.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), isothiocyanato-1,3- dimethoxybenzene (Example 28.0), and(1s,3s)-3- chlorocyclobutane-1- carbohydrazide and (1r,3r)-3-chlorocyclobutane-1- carbohydrazide (Example 153.1).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1r,3S)-3-chlorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1s,3R)-3-chlorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz,DMSO-d₆) δ 12.74-12.96 (m, 1 H) 8.81-9.05 (m, 2 H) 7.57 (br d, J = 2.2Hz, 1 H) 6.77-6.94 (m, 2 H) 4.73-4.78 (m, 1 H) 4.39-4.51 (m, 1 H) 4.31-4.38 (m, 1 H) 3.74 (m, 6 H) 3.39 (dd, J = 7.0, 4.4 Hz, 1 H) 3.14 (s, 3H) 2.77-2.91 (m, 1 H) 2.58 (br d, J = 5.7 Hz, 2 H) 2.38-2.44 (m, 1 H)1.09-1.16 (m, 3 H). LCMS-ESI (pos.) m/z: 541.0 (M + H)⁺. 155.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), isothiocyanato-1,3- dimethoxybenzene (Example 28.0), and(1s,3s)-3- methoxycyclobutane-1- carbohydrazide and (1r,3r)-3-methoxycyclobutane-1- carbohydrazide (Example 154.1).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1r,3S)-3-methoxycyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1s,3R)-3-methoxycyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz,DMSO-d₆) δ 12.67-12.88 (m, 1 H) 8.87-9.04 (m, 2 H) 7.50 (t, J = 8.5 Hz,1 H) 6.84 (dd, J = 8.6, 1.3 Hz, 2 H) 4.76 (d, J = 4.4 Hz, 1 H) 3.82-4.05(m, 1 H) 3.39 (dd, J = 6.9, 4.2 Hz, 1 H) 3.11-3.17 (m, 3 H) 3.05-3.10(m, 3 H) 2.85-2.97 (m, 1 H) 2.35-2.41 (m, 2 H) 1.94-2.06 (m, 2 H)1.09-1.16 (m, 3 H). LCMS-ESI (pos.) m/z: 553.2 (M + H)⁺. 156.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), isothiocyanato-1,3- dimethoxybenzene (Example 28.0), and(1s,3s)-3- methoxycyclobutane-1- carbohydrazide and (1r,3r)-3-methoxycyclobutane-1- carbohydrazide (Example 154.1).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1r,3S)-3-methoxycyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1s,3R)-3-methoxycyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz,DMSO-d₆) δ 12.63-12.84 (m, 1 H) 8.80-8.98 (m, 2 H) 7.37-7.63 (m, 1 H)6.70-7.04 (m, 2 H) 4.65-4.81 (m, 1 H) 3.68-3.78 (m, 7 H) 3.35-3.45 (m, 1H) 3.17 (d, J = 5.3 Hz, 3 H) 3.07 (s, 3 H) 2.52-2.57 (m, 1 H) 2.16-2.31(m, 2 H) 1.90-2.01 (m, 2 H) 1.08- 1.17 (m, 3 H). LCMS-ESI (pos.) m/z:553.2 (M + H)⁺. 159.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2- sulfonamide (Example 29.3), isothiocyanato-1,3-dimethoxybenzene (Example 28.0), and (S)-2,2- difluorocyclobutane-1-carbohydrazide and (R)-2,2- difluorocyclobutane-1- carbohydrazide(Example 159.1). The sample was purified by Chiral SFC: Column:Chiralpak AD-H 2 × 25 cm + Chiralpak AD-H 2 × 25 using 35% MeOH, 40mL/min, Wavelength: 215 nm. Under these conditions, this was the firstpeak to elute.

 

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((R)-2,2-difluorocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((S)-2,2-difluorocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (400 MHz, CDCl₃) δ10.80-11.15 (m, 1 H) 8.62- 8.78 (m, 2 H) 7.30-7.51 (m, 1 H) 6.64 (dd, J= 8.6, 4.7 Hz, 2 H) 4.91-4.99 (m, 1 H) 3.80 (s, 3 H) 3.74 (s, 3 H) 3.69(dd, J = 7.0, 4.8 Hz, 1 H) 3.48-3.57 (m, 1 H) 3.32 (s, 3 H) 2.39-2.60(m, 3 H) 2.08 (br s, 1 H) 1.34-1.40 (m, 3 H). LCMS-ESI (pos.) m/z: 559.2(M + H)⁺. 160.0 (1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2-sulfonamide (Example 29.3), isothiocyanato-1,3- dimethoxybenzene(Example 28.0), and (S)-2,2- difluorocyclobutane-1- carbohydrazide and(R)-2,2- difluorocyclobutane-1- carbohydrazide (Example 159.1). Thesample was purified by Chiral SFC: Column: Chiralpak AD-H 2 × 25 cm +Chiralpak AD-H 2 × 25 using 35% MeOH, 40 mL/ min, Wavelength: 215 nm.Under these conditions, this was the second peak to elute.

 

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((R)-2,2-difluorocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((S)-2,2-difluorocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (400 MHz, CDCl₃) δ8.64-8.72 (m, 2 H) 7.33- 7.45 (m, 1 H) 6.56-6.68 (m, 2 H) 4.93-5.01 (m,1 H) 3.76-3.81 (m, 3 H) 3.73-3.76 (m, 3 H) 3.64-3.73 (m, 1 H) 3.50 (brd, J = 2.4 Hz, 1 H) 3.32 (s, 3 H) 2.39-2.60 (m, 3 H) 2.01-2.13 (m, 1 H)1.31-1.39 (m, 3 H). LCMS-ESI (pos.) m/z: 559.2 (M + H)⁺. 162.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and (1s,3s)-3- fluorocyclobutane-1- carbohydrazide and (1r,3r)-3-fluorocyclobutane-1- carbohydrazide (Example 151.1).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1s,3R)-3-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1r,3S)-3-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz,DMSO-d₆) δ 12.94-13.14 (m, 1 H) 8.84-8.99 (m, 2 H) 8.60-8.76 (m, 1 H)4.84-5.08 (m, 1 H) 4.77 (d, J = 4.0 Hz, 1 H) 3.92-3.97 (m, 6 H) 3.40(qd, J = 6.9, 4.3 Hz, 1 H) 3.08-3.16 (m, 3 H) 2.67-2.79 (m, 1 H)2.51-2.55 (m, 2 H) 2.21-2.40 (m, 2 H) 1.10-1.18 (m, 3 H). LCMS-ESI(pos.) m/z: 543.0 (M + H)⁺. 163.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2- sulfonamide (Example 29.3), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1), and (1s,3s)-3-fluorocyclobutane-1- carbohydrazide and (1r,3r)-3- fluorocyclobutane-1-carbohydrazide (Example 151.1).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1s,3R)-3-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1r,3S)-3-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz,DMSO-d₆) δ 12.94-13.12 (m, 1 H) 8.85-9.03 (m, 2 H) 8.59-8.79 (m, 1 H)5.02-5.36 (m, 1 H) 4.70-4.83 (m, 1 H) 3.97 (m, 6 H) 3.36-3.46 (m, 1 H)3.19-3.29 (m, 1 H) 3.10-3.14 (m, 3 H) 2.52-2.59 (m, 2 H) 2.33-2.44 (m, 2H) 1.10-1.15 (m, 3 H). LCMS-ESI (pos.) m/z: 543.0 (M + H)⁺. 164.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and (1s,3s)-3- chlorocyclobutane-1- carbohydrazide and (1r,3r)-3-chlorocyclobutane-1- carbohydrazide (Example 153.1).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1s,3R)-3-chlorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1r,3S)-3-chlorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz,DMSO-d₆) δ 12.91-13.18 (m, 1 H) 8.83-9.00 (m, 2 H) 8.58-8.76 (m, 1 H)4.72-4.88 (m, 1 H) 4.35-4.57 (m, 1 H) 3.88-4.03 (m, 6 H) 3.36-3.45 (m, 1H) 3.08-3.15 (m, 3 H) 2.98-3.08 (m, 1 H) 2.65- 2.76 (m, 2 H) 2.37-2.43(m, 2 H) 1.09-1.17 (m, 3 H). LCMS-ESI (pos.) m/z: 559.0 (M + H)⁺. 165.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and (1s,3s)-3- chlorocyclobutane-1- carbohydrazide and (1r,3r)-3-chlorocyclobutane-1- carbohydrazide (Example 153.1).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1s,3R)-3-chlorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1r,3S)-3-chlorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz,DMSO-d₆) δ 12.97-13.16 (m, 1 H) 8.85-9.03 (m, 2 H) 8.64-8.85 (m, 1 H)4.70-4.82 (m, 1 H) 4.56-4.70 (m, 1 H) 3.95 (m, 6 H) 3.36-3.51 (m, 2 H)3.12-3.16 (m, 3 H) 2.74-2.82 (m, 2 H) 2.43-2.48 (m, 2 H) 1.08-1.16 (m, 3H). LCMS-ESI (pos.) m/z: 559.0 (M + H)⁺. 166.0(2S,3R)-3-(5-chloropyrimidin-2- yl)butane-2-sulfonamide (Example 27.4),5-isothiocyanato- 4,6-dimethoxypyrimidine (Example 28.1), and 2-(difluoromethyl)cyclobutanecarbo- hydrazide (Example 146.1).

(2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(5-((1R,2S)-2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)butane-2-sulfonamide and(2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(5-((1S,2R)-2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)butane-2-sulfonamide and(2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(5-((1R,2R)-2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)butane-2-sulfonamide and(2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(5-((1S,2S)-2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)butane-2-sulfonamide. ¹H NMR (500 MHz,DMSO-d₆) δ 12.93-13.22 (m, 1 H) 8.85-8.91 (m, 2 H) 8.66-8.70 (m, 1 H)6.02 (s, 1 H) 3.92 (m, 6 H) 3.49-3.67 (m, 2 H) 3.19 (d, J = 8.4 Hz, 1 H)2.96- 3.12 (m, 1 H) 1.80-2.13 (m, 4 H) 1.11 (d, J = 7.0 Hz, 3 H).LCMS-ESI (pos.) m/z: 559.1 (M + H)⁺. 167.0(1S,2S)-1-(5-chloropyrimidin-2- yl)-1-isopropoxypropane-2- sulfonamide(Example 31.01), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 2- (difluoromethyl)cyclobutane- carbohydrazide (Example146.1). The sample was purified by Chiral SFC: Chiralpak AD-H MobilePhase: 25% IPA, Flow rate: 80 mL/min, Pressure Drop: 84 bar, BPR: 100bar, UV Detector Wavelength: 217 nm. Under these conditions, this wasthe first peak to elute.

 

(1S,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1R,2S)-2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-isopropoxypropane-2- sulfonamide or(1S,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1S,2R)-2-(difluoromethyl)cyclobutyl)-4-(2,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-isopropoxypropane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 12.81-13.03(m, 1 H) 8.85-8.98 (m, 2 H) 8.64-8.78 (m, 1 H) 5.84-6.20 (m, 1 H)4.68-4.86 (m, 1 H) 3.87-4.03 (m, 6 H) 3.37-3.46 (m, 2 H) 3.18 (q, J =8.3 Hz, 1 H) 2.97-3.12 (m, 1 H) 1.95- 2.10 (m, 3 H) 1.82-1.95 (m, 1 H)0.78-0.83 (m, 3 H). LCMS-ESI (pos.) m/z: 603.1 (M + H)⁺. 168.0(1S,2S)-1-(5-chloropyrimidin-2- yl)-1-isopropoxypropane-2- sulfonamide(Example 31.01), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and 2- (difluoromethyl)cyclobutane- carbohydrazide (Example146.1). The sample was purified by Chiral SFC: Chiralpak AD-H MobilePhase: 25% IPA, Flow rate: 80 mL/min, Pressure Drop: 84 bar, BPR: 100bar, UV Detector Wavelength: 217 nm Under these conditons, this was thesecond peak to elute.

 

(1S,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1R,2S)-2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-isopropylpropane-2- sulfonamide or(1S,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1S,2R)-2-(difluoromethyl)cyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-isopropoxypropane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d6) δ 12.77-13.08(m, 1 H) 8.87-9.04 (m, 2 H) 8.56-8.87 (m, 1 H) 5.84-6.25 (m, 1 H) 4.75(d, J = 6.9 Hz, 1 H) 3.96 (m, 6 H) 3.38-3.46 (m, 2 H) 3.18 (s, 1 H)2.98-3.14 (m, 1 H) 1.94-2.10 (m, 3 H) 1.81-1.94 (m, 1 H) 0.82 (d, J =6.1 Hz, 3 H). LCMS-ESI (pos.) m/z: 603.1 (M + H)⁺. 169.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), isothiocyanato-1,3- dimethoxybenzene (Example 28.0), and2-cyanocyclobutane-1- carbohydrazide (Example 169.1). The sample waspurified by Chiral SFC Chiralpak AS-H 2 × 25 cm. Mobile Phase: 25% MeOH,Flow rate: 80 mL/min, Pressure Drop: 92 bar, BPR: 100 bar, UV DetectorWavelength: 215 nm. Under these conditions, this was the first peak toelute.

 

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1R,2S)-2-cyanocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1S,2R)-2-cyanocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, CDCl₃) δ10.82-11.12 (m, 1 H) 8.71 (s, 2 H) 7.41-7.49 (m, 1 H) 6.68 (dd, J =17.5, 8.6 Hz, 2 H) 4.92-4.96 (m, 1 H) 3.78-3.87 (m, 6 H) 3.66-3.76 (m, 1H) 3.36-3.41 (m, 2 H) 3.29-3.34 (m, 3 H) 2.45-2.60 (m, 1 H) 2.26-2.42(m, 2 H) 2.07-2.23 (m, 1 H) 1.36 (d, J = 7.0 Hz, 3 H). LCMS-ESI (pos.)m/z: 548.2 (M + H)⁺. 170.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2- sulfonamide (Example 29.3), isothiocyanato-1,3-dimethoxybenzene (Example 28.0), and 2-cyanocyclobutane-1-carbohydrazide (Example 169.1). The sample was purified by Chiral SFCChiralpak AS-H 2 × 25 cm. Mobile Phase: 25% MeOH, Flowrate: 80 mL/min,Pressure Drop: 92 bar, BPR: 100 bar UV Detector Wavelength: 215 nm.Under these conditions, this was the second peak to elute.

 

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1R,2R)-2-cyanocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1R,2R)-2-cyanocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, CDCl₃) δ10.76-11.12 (m, 1 H) 8.57- 8.95 (m, 2 H) 7.34-7.71 (m, 1 H) 6.67 (dd, J= 12.3, 8.5 Hz, 2 H) 4.80-5.09 (m, 1 H) 3.83-3.89 (m, 3 H) 3.78- 3.83(m, 3 H) 3.67-3.73 (m, 1 H) 3.36-3.43 (m, 2 H) 3.34 (s, 3 H) 2.51 (br d,J = 9.7 Hz, 1 H) 2.26-2.43 (m, 2 H) 2.10-2.23 (m, 1 H) 1.36 (d, J = 6.9Hz, 3 H). LCMS- ESI (pos.) m/z: 548.2 (M + H)⁺. 175.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and (1s,4s)-4- fluorocyclohexane-1- carbohydrazide and (1r,4r)-4-fluorocyclohexane-1- carbohydrazide (Example 175.1).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1s,4R)-4-fluorocyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1r,4S)-4-fluorocyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz,DMSO-d₆) δ 8.88-9.05 (m, 2 H) 8.63-8.80 (m, 1 H) 4.77 (d, J = 4.0 Hz, 1H) 4.37-4.71 (m, 1 H) 3.89-4.04 (m, 6 H) 3.36-3.44 (m, 1 H) 3.12 (s, 3H) 2.31-2.39 (m, 1 H) 1.99 (br d, J = 3.9 Hz, 2 H) 1.73- 1.83 (m, 2 H)1.47 (br s, 4 H) 1.11 (d, J = 7.0 Hz, 3 H) LCMS-ESI (pos.) m/z: 571.0(M + H)⁺. 176.0 (1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2-sulfonamide (Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine(Example 28.1), and (1s,4s)-4- fluorocyclohexane-1- carbohydrazide and(1r,4r)-4- fluorocyclohexane-1- carbohydrazide (Example 175.1).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1s,4R)-4-fluorocyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1r,4S)-4-fluorocyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz,DMSO-d₆) δ 12.89-13.12 (m, 1 H) 8.85-8.99 (m, 2 H) 8.64-8.85 (m, 1 H)4.67-5.03 (m, 2 H) 3.88-4.03 (m, 6 H) 3.35-3.47 (m, 1 H) 3.09-3.15 (m, 3H) 2.41-2.47 (m, 1 H) 1.85-1.93 (m, 2 H) 1.49- 1.75 (m, 6 H) 1.12 (d, J= 7.0 Hz, 3 H) LCMS-ESI (pos.) m/z: 571.0 (M + H)⁺. 177.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and (1s,3s)-3- (trifluoromethyl)cyclobutane-1- carbohydrazide and(1r,3r)-3- (trifluoromethyl)cyclobutane-1- carbohydrazide (Example149.1).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1s,3R)-3-(trifluoromethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1r,3S)-3-(trifluoromethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆)δ 13.02-13.23 (m, 1 H) 8.88-9.00 (m, 2 H) 8.64-8.81 (m, 1 H) 4.65-4.86(m, 1 H) 3.87-3.99 (m, 6 H) 3.37-3.45 (m, 1 H) 3.21-3.30 (m, 2 H)3.11-3.17 (m, 3 H) 2.46-2.49 (m, 2 H) 2.27- 2.35 (m, 2 H) 1.08-1.17 (m,3 H). LCMS-ESI (pos.) m/z: 593.0 (M + H)⁺. 178.0(1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2- sulfonamide(Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example28.1), and (1s,3s)-3- (trifluoromethyl)cyclobutane-1- carbohydrazide and(1r,3r)-3- (trifluoromethyl)cyclobutane-1- carbohydrazide (Example149.1).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1s,3R)-3-(trifluoromethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1r,3S)-3-(trifluoromethyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆)δ 12.92-13.11 (m, 1 H) 8.87-8.99 (m, 2 H) 8.62-8.82 (m, 1 H) 4.70-4.82(m, 1 H) 3.88-3.99 (m, 6 H) 3.38-3.43 (m, 1 H) 3.22-3.27 (m, 1 H)3.11-3.21 (m, 4 H) 2.20-2.33 (m, 4 H) 1.11- 1.16 (m, 3 H). LCMS-ESI(pos.) m/z: 593.0 (M + H)⁺. 179.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2- sulfonamide (Example 29.3), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1), and2-fluorocyclobutane-1- carbohydrazide (Example 179.1). The sample waspurified by Chiral SFC Chiralcel OX-H 2 × 25 cm. Mobile Phase: 40% IPA,Flow rate: 80 mL/min, Pressure Drop: 98 bar, BPR: 100 bar, UV DetectorWavelength: 218 nm Under these conditions this was the first peak toelute.

 

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1S,2S)-2-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1R,2R)-2-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, CDCl₃) δ 10.82-11.14 (m,1 H) 8.66- 8.80 (m, 2 H) 8.36-8.53 (m, 1 H) 4.99 (d, J = 4.7 Hz, 1 H)4.78-4.96 (m, 1 H) 3.96-4.04 (m, 6 H) 3.64-3.75 (m, 1 H) 3.40 (br s, 1H) 3.32-3.36 (m, 3 H) 2.59-2.68 (m, 1 H) 2.31-2.55 (m, 2 H) 1.92-2.04(m, 1 H) 1.36 (d, J = 7.0 Hz, 3 H). LCMS-ESI (pos.) m/z: 543.0 (M + H)⁺.180.0 (1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2-sulfonamide (Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine(Example 28.1), and 2-fluorocyclobutane-1- carbohydrazide (Example179.1). The sample was purified by Chiral SFC Chiralcel OX-H 2 × 25 cm,Mobile Phase: 40% IPA Flowrate: 80 mL/min, Pressure Drop: 98 bar, BPR:100 bar, UV Detector Wavelength: 218 nm. Under these conditions, thiswas the first peak to elute.

 

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1S,2S)-2-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1R,2R)-2-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, CDCl₃) δ 10.76-11.08 (m,1 H) 8.61- 8.83 (m, 2 H) 8.43-8.61 (m, 1 H) 4.96-5.00 (m, 1 H) 4.78-4.96(m, 1 H) 3.99 (m, 6 H) 3.72 (dd, J = 6.9, 4.7 Hz, 1 H) 3.38-3.45 (m, 1H) 3.31-3.36 (m, 3 H) 2.59-2.69 (m, 1 H) 2.31-2.52 (m, 2 H) 1.91-2.01(m, 1 H) 1.38 (d, J = 7.0 Hz, 3 H). LCMS-ESI (pos.) m/z: 543.0 (M + H)⁺.181.0 (1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2-sulfonamide (Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine(Example 28.1), and 2-fluorocyclobutane-1- carbohydrazide (Example179.1). The sample was purified by Chiral SFC Chiralcel OX-H 2 × 25 cm,Mobile Phase: 40% IPA, Flowrate: 80 mL/min, Pressure Drop: 98 bar, BPR:100 bar, UV Detector Wavelength: 218 nm. Under these conditions, thiswas the first peak to elute.

 

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1R,2S)-2-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1S,2R)-2-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz,DMSO-d₆) δ 12.96-13.24 (m, 1 H) 8.82-9.00 (m, 2 H) 8.68 (s, 1 H)4.87-5.06 (m, 1 H) 4.77 (d, J = 4.2 Hz, 1 H) 3.94 (m, 6 H) 3.33-3.45 (m,2 H) 3.13 (s, 3 H) 2.15-2.28 (m, 1 H) 1.86-2.11 (m, 2 H) 1.58- 1.71 (m,1 H) 1.14 (d, J = 7.0 Hz, 3 H). LCMS-ESI (pos.) m/z: 543.0 (M + H)⁺.182.0 (1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2-sulfonamide (Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine,(Example 28.1), and 2-fluorocyclobutane-1- carbohydrazide (Example179.1). The sample was purified by Chiral SFC Chiralcel OX-H 2 × 25 cm,Mobile Phase: 40% IPA, Flowrate: 80 mL/min, Pressure Drop: 98 bar, BPR:100 bar, UV Detector Wavelength: 218 nm. Under these conditions, thiswas the second peak to elute.

 

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1R,2S)-2-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1S,2R)-2-fluorocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz,DMSO-d₆) δ 12.99-13.16 (m, 1 H) 8.83-8.99 (m, 2 H) 8.56-8.73 (m, 1 H)4.83-5.10 (m, 1 H) 4.66-4.83 (m, 1 H) 3.96 (s, 3 H) 3.93 (s, 3 H) 3.32-3.46 (m, 2 H) 3.13 (s, 3 H) 2.16-2.27 (m, 1 H) 1.88-2.13 (m, 2 H)1.58-1.74 (m, 1 H) 1.14 (d, J = 7.0 Hz, 3 H). LCMS-ESI (pos.) m/z: 543.0(M + H)⁺. 187.0 (1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2-sulfonamide (Example 29.3), 5- isothiocyanato-4,6- dimethoxypyrimidine(Example 28.1), and 2-methylcyclobutane-1- carbohydrazide (Example188.1). The sample was purified through 3 Chiral SFC Chiralpak AS-H 2 ×25 cm columns Mobile Phase: 25% IPA, Flowrate: 40 mL/min, Pressure Drop:140 bar, BPR: 100 bar, UV Detector Wavelength: 220 nm. Under theseconditions, this was the first peak to elute

 

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1S,2S)-2-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1- methoxypropane-2-sulfonamideor (1R,2S)-1-(5- chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1R,2R)-2-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ12.78-13.03 (m, 1 H) 8.85-9.00 (m, 2 H) 8.58-8.75 (m, 1 H) 4.73-4.82 (m,1 H) 3.95 (m, 6 H) 3.35-3.44 (m, 1 H) 3.10-3.15 (m, 3 H) 2.51-2.58 (m, 1H) 1.85-2.03 (m, 5 H) 1.10-1.15 (m, 3 H) 0.85-0.89 (m, 3 H). LCMS-ESI(pos.) m/z: 539.1 (M + H)⁺. 188.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2- sulfonamide (Example 29.3), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1), and (1R,2S)-2-methylcyclobutane-1- carbohydrazide and (1S,2R)-2- methylcyclobutane-1-carbohydrazide and (1S,2S)-2- methylcyclobutane-1- carbohydrazide and(1R,2R)-2- methylcyclobutane-1- carbohydrazide (Example 188.1). Thesample was purified through 3 Chiral SFC Chiralpak AS-H 2 × 25 cmcolumns. Mobile Phase: 25% IPA Flowrate: 40 mL/min, Pressure Drop: 140bar, BPR: 100 bar, UV Detector Wavelength: 220 nm. Under theseconditions, this was the second peak to elute.

 

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1S,2R)-2-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1- methoxypropane-2-sulfonamideor (1R,2S)-1-(5- chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1R,2S)-2-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d6) δ 12.86-13.03(m, 1 H) 8.93 (s, 2 H) 8.70 (s, 1 H) 4.58-4.89 (m, 1 H) 3.86-4.02 (m, 6H) 3.33-3.49 (m, 1 H) 3.10-3.17 (m, 3 H) 2.62- 2.72 (m, 1 H) 2.53 (s, 1H) 1.83-2.04 (m, 3 H) 1.44-1.57 (m, 1 H) 1.13 (d, J = 7.0 Hz, 3 H) 0.85(d, J = 6.6 Hz, 3 H). LCMS-ESI (pos.) m/z: 539.1 (M + H)⁺. 191.0(1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propane-2- sulfonamide(Example 29.0), isothiocyanato-1,3- dimethoxybenzene (Example 28.0), and(1s,3s)-3- chlorocyclobutane-1- carbohydrazide and (1r,3r)-3-chlorocyclobutane-1- carbohydrazide (Example 153.1).

(1R,2S)-N-(5-((1r,3S)-3-chlorocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide or (1R,2S)-N-(5-((1s,3R)-3-chlorocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d6) δ12.72-12.94 (m, 1 H) 8.57-8.67 (m, 2 H) 7.50 (t, J = 8.5 Hz, 1 H) 6.84(dd, J = 8.6, 1.8 Hz, 2 H) 4.79 (d, J = 3.5 Hz, 1 H) 4.36-4.56 (m, 1 H)3.73 (m, 6 H) 3.38 (dd, J = 7.0, 3.6 Hz, 1 H) 3.14 (s, 3 H) 2.82 (s, 1H) 2.59 (br dd, J = 7.7, 4.1 Hz, 2 H) 2.35- 2.42 (m, 2 H) 2.26 (s, 3 H)1.11 (d, J = 7.0 Hz, 3 H). LCMS-ESI (pos.) m/z: 537.2 (M + H)⁺. 192.0(1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propane-2- sulfonamide(Example 29.0), isothiocyanato-1,3- dimethoxybenzene (Example 28.0), and(1s,3s)-3- chlorocyclobutane-1- carbohydrazide and (1r,3r)-3-chlorocyclobutane-1- carbohydrazide (Example 153.1).

(1R,2S)-N-(5-((1r,3S)-3-chlorocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide or (1R,2S)-N-(5-((1s,3R)-3-chlorocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ12.67-12.96 (m, 1 H) 8.45-8.75 (m, 2 H) 7.37-7.66 (m, 1 H) 6.84 (dd, J =8.6, 1.9 Hz, 2 H) 4.69-4.82 (m, 1 H) 4.50-4.69 (m, 1 H) 3.67- 3.81 (m, 6H) 3.37 (qd, J = 7.0, 3.6 Hz, 1 H) 3.23 (dt, J = 9.7, 4.6 Hz, 1 H) 3.14(s, 3 H) 2.75 (br d, J = 7.4 Hz, 2 H) 2.31-2.41 (m, 2 H) 2.26 (s, 3 H)1.11 (d, J = 7.0 Hz, 3 H). LCMS-ESI (pos.) m/z: 537.2 (M + H)⁺. 193.0(2S,3R)-3-(5-methylpyrimidin-2- yl)butane-2-sulfonamide (Example 27.0),isothiocyanato- 1,3-dimethoxybenzene, (Example 28.0), and (1s,3s)-3-chlorocyclobutane-1- carbohydrazide and (1r,3r)-3- chlorocyclobutane-1-carbohydrazide (Example 153.1).

(2S,3R)-N-(5-((1r,3S)-3-chlorocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide or (2S,3R)-N-(5-((1s,3R)-3-chlorocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane- 2-sulfonamide.¹H NMR (500 MHz, DMSO-d₆) δ 12.68-12.93 (m, 1 H) 8.58 (s, 2 H) 7.42-7.60(m, 1 H) 6.83 (dd, J = 8.6, 2.5 Hz, 2 H) 4.61 (s, 1 H) 3.67-3.80 (m, 6H) 3.60-3.67 (m, 1 H) 3.55 (qd, J = 6.9, 3.4 Hz, 1 H) 3.17-3.28 (m, 1 H)2.72- 2.88 (m, 2 H) 2.32-2.40 (m, 2 H) 2.17-2.29 (m, 3 H) 1.22 (d, J =7.1 Hz, 3 H) 1.02-1.18 (m, 3 H). LCMS-ESI (pos.) m/z: 521.2 (M + H)⁺.194.0 (2S,3R)-3-(5-methylpyrimidin-2- yl)butane-2-sulfonamide (Example27.0), isothiocyanato- 1,3-dimethoxybenzene, (Example 28.0), and(1s,3s)-3- chlorocyclobutane-1- carbohydrazide and (1r,3r)-3-chlorocyclobutane-1- carbohydrazide (Example 153.1).

(2S,3R)-N-(5-((1r,3S)-3-chlorocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide or (2S,3R)-N-(5-((1s,3R)-3-chlorocyclobutyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane- 2-sulfonamide.¹H NMR (500 MHz, DMSO-d₆) δ 12.77-12.99 (m, 1 H) 8.58 (s, 2 H) 7.50 (t,J = 8.5 Hz, 1 H) 6.83 (dd, J = 8.6, 2.2 Hz, 2 H) 4.33-4.50 (m, 1 H) 3.72(m, 6 H) 3.61-3.69 (m, 1 H) 3.50-3.60 (m, 1 H) 2.77-2.90 (m, 1 H)2.54-2.62 (m, 2 H) 2.35-2.43 (m, 2 H) 2.23 (s, 3 H) 1.22 (d, J = 7.1 Hz,3 H) 1.07 (d, J = 7.0 Hz, 3 H). LCMS-ESI (pos.) m/z: 521.2 (M + H)⁺.200.0 (1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propane-2-sulfonamide (Example 29.0), isothiocyanato-1,3- dimethoxybenzene(Example 28.0), and spiro[2.3]hexane-5- carbohydrazide (Example 200.1).

201.0 (1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propane-2-sulfonamide, (Example 29.0), 5- isothiocyanato-4,6- dimethoxypyrimidine(Example 28.1), and spiro[2.3]hexane-5- carbohydrazide (Example 200.1).

202.0 (2S,3R)-3-(5-methylpyrimidin-2- yl)butane-2-sulfonamide (Example27.0), 5-isothiocyanato- 4,6-dimethoxypyrimidine (Example 28.1), andspiro[2.3]hexane-5-carbohydrazide (Example 200.1).

208.0 (1R,2S)-1-(5-chloropyrimidin-2- yl)-1-methoxypropane-2-sulfonamide (Example 29.3), isothiocyanato-1,3- dimethoxybenzene(Example 28.0), and 2-methylcyclobutane-1- carbohydrazide (Example200.1).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,2R)-2-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1S,2R)-2-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1S,2S)-2-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,2S)-2-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ 12.63-12.87 (m, 1 H) 8.85-8.94 (m, 2 H) 7.39-7.60 (m, 1 H)6.75-7.00 (m, 2 H) 4.72-4.84 (m, 1 H) 3.71-3.79 (m, 6 H) 3.35-3.45 (m, 1H) 3.15 (d, J = 0.9 Hz, 3 H) 2.41-2.49 (m, 2 H) 1.77- 2.09 (m, 3 H)1.40-1.57 (m, 1 H) 1.13 (d, J = 7.0 Hz, 3 H) 0.73-0.80 (m, 3 H).LCMS-ESI (pos.) m/z: 537.1 (M + H)⁺. 209.0(1R,2S)-1-(2,2-difluoroethoxy)-1- (5-methylpyrimidin-2-yl)propane-2-sulfonamide (Example 209.2), isothiocyanato-1,3- dimethoxybenzene(Example 28.0), and cyclobutanecarbohydrazide (commercially availablefrom ChemBridge Corporation).

Example 209.2. Preparation of(1R,2S)-1-(2,2-difluoroethoxy)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide

N-Methoxy-N,5-dimethylpyrimidine-2-carboxamide, Example 209.1

To a solution of 5-methylpyrimidine-2-carboxylic acid (1 g, 7.24 mmol)in DMF (72.4 mL) was added 5-methylpyrimidine-2-carboxylic acid (1 g,7.24 mmol), and N,O-dimethylhydroxylamine hydrochloride (0.777 g, 7.96mmol). The mixture was cooled to 0° C. and 1-propanephosphonic acidcyclic anhydride, 50 wt. % solution in EtOAc (9.21 mL, 14.48 mmol) wasadded dropwise. The mixture was allowed to warm to RT overnight. LCMSindicated complete conversion to product. The mixture was diluted withwater, extracted with CHCl₃:IPA (3:1) and washed with brine and NaHCO₃.The mixture was then dried over Na₂SO₄, concentrated in vacuo andpurified by silica gel chromatography (0-100% heptanes:EtOAc) to yieldExample 209.11 (0.7 g, 3.86 mmol, 53.4% yield). ¹H NMR (500 MHz, CDCl₃)δ 8.61-8.69 (m, 2H) 3.61-3.79 (m, 3H) 3.27-3.47 (m, 3H) 2.34-2.45 (m,3H). LCMS-ESI (pos) m/z: 182.2 (M+H)⁺.

(R)—N,N-Bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)-1-oxopropane-2-sulfonamideand(S)—N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)-1-oxopropane-2-sulfonamide,Example 31.2

A solution of N,N-bis(4-methoxybenzyl)ethanesulfonamide (azeotropedthree times with toluene before use) (Example 30.0, 0.771 g, 2.21 mmol)was dissolved in THF (3.68 mL) and then cooled to −78° C. using a dryice acetone bath (internal reaction temperature/bath temperature notmonitored). To this was added a solution of n-butyllithium (0.883 mL,2.21 mmol, 2.5 M in hexanes). The reaction turned pink immediately andthen slowly faded to yellow upon stirring at −78° C. for 30 mins. Thissolution was then added quickly to a solution ofN-methoxy-N,5-dimethylpyrimidine-2-carboxamide (Example 209.11, 0.2 g,1.104 mmol) in THF (0.5 mL) at RT. The reaction was stirred at RT for−20 mins after which LCMS indicated complete consumption of Weinrebamide and conversion to product. The reaction was quenched by additionto separation funnel that contained 1M HCl (˜15 mL). The mixture wasextracted with DCM, dried over Na₂SO₄ and concentrated in vacuo. Themixture was purified by silica gel chromatography 0-100% EtOAc:heptanesto yield Example 31.2 (0.36 g, 0.767 mmol, 69.5% yield). ¹H NMR (500MHz, DMSO-d₆) δ 8.86-8.93 (m, 2H) 7.06-7.15 (m, 4H) 6.79-6.87 (m, 4H)5.87-5.95 (m, 1H) 4.20-4.34 (m, 4H) 3.67-3.73 (m, 6H) 2.38-2.42 (m, 3H)1.46-1.55 (m, 3H). LCMS-ESI (pos) m/z: 470.0 (M+H)⁺.

(1R,2S)-1-Hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide,Example 209.12

To a solution of Example 31.2 (1.0 g, 2.130 mmol) in DMF (22.18 mL) wasadded(N-((1S,2S)-1,2-diphenyl-2-((3-phenylpropyl)amino)ethyl)-4-methylphenylsulfonamido)ruthenium(II)chloride (9.91 mg, 0.016 mmol). The mixture was then degassed by placingunder vacuum and backfilling with N₂ three times. To this was added asolution of HCOOH:Et₃N (5:2 v/v) (0.55 mL), and the reaction was stirredat RT for 12 hrs after which LCMS indicated complete conversion toproduct and 7:1 d.r. (syn:anti). The mixture was then washed with 5%LiCl (aq), extracted with DCM and then with CHCl₃:IPA (3:1). The organiclayer was dried over Na₂SO₄ and concentrated in vacuo. The mixture wasloaded directly onto a silica gel column and purified using a gradientof 0-100% heptanes:EtOAc. DMF caused both syn and anti to co-elute. Thefactions were combined and concentrated in vacuo. The mixture wasrepurified using the same gradient to yield(1R,2S)-1-hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide(0.77 g, 1.63 mmol, 77% yield) as an off white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.85-8.93 (m, 2H) 7.08-7.15 (m, 4H) 6.78-6.86 (m, 4H)5.86-5.96 (m, 1H) 4.20-4.35 (m, 4H) 3.68-3.75 (m, 6H) 3.28-3.34 (m, 2H)2.37-2.42 (m, 3H) 1.47-1.54 (m, 3H). LCMS-ESI (pos) m/z: 572.2 (M+H)⁺.

(1R,2S)-1-(2,2-Difluoroethoxy)-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide,Example 209.1

A solution of Example 209.12 (0.5 g, 1.06 mmol) in THF (5.30 mL) wascooled to −78° C. To this was added potassium bis(trimethylsilyl)amidesolution, (1M in THF, 1.27 mL, 1.27 mmol) dropwise, and the reaction wasstirred at −78° C. for 15 mins. 2,2-Difluoroethyltrifluoromethanesulfonate (0.056 mL, 0.42 mmol) was added to the mixturedropwise. The reaction was then stirred for another 15 mins at −78° C.after which LCMS indicated complete conversion to product. The mixturewas poured onto a solution of NH₄Cl and extracted with DCM, dried overNa₂SO₄ and concentrated in vacuo. The material was purified by silicagel 0-75% EtOAc:Heptanes to yield Example 209.1 (0.4 g, 0.75 mmol, 70%yield). LCMS-ESI (pos.) m/z: 472.2 (M+H)⁺.

(1R,2S)-1-(2,2-Difluoroethoxy)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide,Example 209.2

To a solution of Example 209.1 (0.8 g, 1.494 mmol) in DCM (7.47 mL) wasadded anisole (0.808 mL, 7.47 mmol), and the mixture was cooled to 0° C.To this was added 1,1,1-trifluoroacetic acid (2.226 mL, 29.9 mmol), andthe mixture was allowed to warm to RT and stirred at RT for 24 h. LCMSindicated incomplete conversion to product and so a second portion ofTFA was added and the mixture stirred for a further 12 h after which thereaction didn't progress any further. The mixture was quenched byaddition to an aqueous solution of NaHCO₃ and extracted with DCM, driedover Na₂SO₄ and concentrated in vacuo. The mixture was purified using agradient of 0-100 Heptanes:EtOAc. to yield Example 209.2 (0.4 g, 1.36mmol, 91% yield). LCMS-ESI (pos.) m/z: 296.0 (M+H)⁺.

Example 161.0. Preparation of(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1s,4R)-4-methoxycyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamideor(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1r,4S)-4-methoxycyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide

(Z)—N-(((1R,2S)-1-(5-Chloropyrimidin-2-yl)-1-methoxypropan-2-yl)sulfonyl)-N′-(2,6-dimethoxyphenyl)hydrazinecarboximidamide,Example 161.1

To a solution of Example 29.3 (0.30 g, 1.13 mmol), in ACN (11.29 mL) wasadded 2-isothiocyanato-1,3-dimethoxybenzene (0.22 g, 1.13 mmol) followedby cesium carbonate (0.48 mL, 1.47 mmol). The mixture was then stirredat RT for 12 h. LCMS indicated complete loss of starting material. Tothe reaction was added 2,2-hydrazine hydrate (0.057 g, 1.13 mmol)followed by silver nitrate (0.088 mL, 2.26 mmol). The mixture wasstirred at RT for 15 mins. LCMS indicated conversion to product. Themixture was loaded directly onto silica gel and purified bychromatography 0-100 heptanes-EtOAc:EtOH (3:1) to yield Example 161.1(0.5 g, 1.09 mmol, 97% yield) as a white solid. LCMS-ESI (pos.) m/z:459.0 (M+H)⁺.

(Z)—N-(((1R,2S)-1-(5-Chloropyrimidin-2-yl)-1-methoxypropan-2-yl)sulfonyl)-N′-(4,6-dimethoxypyrimidin-5-yl)hydrazinecarboximidamide,Example 161.2

To a vial containing Example 29.3 (2 g, 7.53 mmol) was added ACN (75mL). After 10 minutes, 5-isothiocyanato-4,6-dimethoxypyrimidine (1.48 g,7.53 mmol) was added carefully in portions. The mixture was cooled in anice-bath and then cesium carbonate (4.90 g, 15.05 mmol) was addedcarefully in portions to the homogeneous solution. Upon completeaddition of cesium carbonate, the mixture was allowed to warm to 23° C.and monitored with LC-MS. After 12 h, complete loss of starting materialwas observed. After 20 mins, hydrazine, monohydrate (0.45 mL, 5.75 mmol)and then silver nitrate (2.56 g, 15.05 mmol) were carefully added inportions. The mixture was allowed to warm to 23° C. and monitored withLC-MS. After 30 mins. conversion to product was observed by LCMS. Themixture was loaded directly onto silica and purified with a gradient of0-100% EtOH:EtOAc (3:1) in heptanes to yield Example 161.2 (1.58 g, 3.43mmol, 46% yield). LCMS-ESI (pos.) m/z: 461.0 (M+H)⁺.

The compounds set forth in the following table were synthesizedfollowing the procedures described in Example 214.0 using the knownstarting material as described.

TABLE 17 Example Reagents Structure, Name and Data 161.0(Z)-N-(((1R,2S)-1-(5- chloropyrimidin-2-yl)-1-methoxypropan-2-yl)sulfonyl)-N′- (4,6-dimethoxypyrimidin-5-yl)hydrazinecarboximidamide (Example 161.2), and 4-4-methoxycyclohexane-1-carboxylic acid (commercially available fromEnamine).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1s,4R)-4-methoxycyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1r,4S)-4-methoxycyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ12.82-13.10 (m, 1 H) 8.83-9.04 (m, 2 H) 8.60-8.80 (m, 1 H) 4.70-4.82 (m,1 H) 3.88-4.02 (m, 6 H) 3.34-3.41 (m, 1 H) 3.17- 3.21 (m, 3 H) 3.04-3.14(m, 4 H) 2.23-2.33 (m, 1 H) 1.92-2.02 (m, 2 H) 1.69-1.78 (m, 2 H) 1.43(br d, J = 12.2 Hz, 2 H) 1.04-1.15 (m, 5 H) LCMS-ESI (pos.) m/z: 583.0(M + H)⁺. 172.0 (Z)-N-(((1R,2S)-1-(5- chloropyrimidin-2-yl)-1-methoxypropan-2-yl)sulfonyl)-N′- (4,6-dimethoxypyrimidin-5-yl)hydrazinecarboximidamide (Example 161.2), and 4-(trifluoromethyl)cyclohexane-1- carboxylic acid (commercially availablefrom Enamine).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1s,4R)-4-(trifluoromethyl)cyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1r,4S)-4-(trifluoromethyl)cyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆)δ 12.89-13.05 (m, 1 H) 8.93 (s, 2 H) 8.70 (s, 1 H) 4.77 (d, J = 4.0 Hz,1 H) 3.91-4.05 (m, 6 H) 3.37 (br dd, J = 6.8, 4.1 Hz, 1 H) 3.11 (s, 3 H)2.22-2.45 (m, 2 H) 1.74-1.88 (m, 4 H) 1.50 (br d, J = 12.8 Hz, 2 H)1.24-1.36 (m, 2 H) 1.12 (d, J = 7.0 Hz, 3 H). LCMS-ESI (pos.) m/z: 621.0(M + H)⁺. 173.0 (Z)-N-(((1R,2S)-1-(5- chloropyrimidin-2-yl)-1-methoxypropan-2-yl)sulfonyl)-N′- (4,6-dimethoxypyrimidin-5-yl)hydrazinecarboximidamide (Example 161.2), and 4-(trifluoromethyl)cyclohexane-1- carboxylic acid (commercially availablefrom Enamine).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1s,4R)-4-(trifluoromethyl)cyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1r,4S)-4-(trifluoromethyl)cyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆)δ 12.91-13.06 (m, 1 H) 8.93 (s, 2 H) 8.60-8.75 (m, 1 H) 4.67-4.90 (m, 1H) 3.86-4.05 (m, 6 H) 3.36 (br dd, J = 7.0, 3.9 Hz, 1 H) 3.12 (s, 3 H)2.69-2.75 (m, 1 H) 2.27-2.38 (m, 1 H) 1.56-1.77 (m, 8 H) 1.07-1.14 (m, 3H). LCMS-ESI (pos.) m/z: 621.0 (M + H)⁺. 174.0 (Z)-N-(((1R,2S)-1-(5-chloropyrimidin-2-yl)-1- methoxypropan-2-yl)sulfonyl)-N′-(4,6-dimethoxypyrimidin-5- yl)hydrazinecarboximidamide (Example 161.2),and 4-4- methoxycyclohexane-1-carboxylic acid (commercially availablefrom Enamine).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1s,4R)-4-methoxycyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1r,4S)-4-methoxycyclohexyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ12.78-13.03 (m, 1 H) 8.91-9.00 (m, 2 H) 8.64-8.78 (m, 1 H) 4.78 (d, J =4.0 Hz, 1 H) 3.85-4.15 (m, 6 H) 3.33 -3.40 (m, 1 H) 3.15-3.21 (m, 3 H)3.11 (s, 3 H) 2.31-2.40 (m, 1 H) 1.74-1.82 (m, 2 H) 1.60-1.72 (m, 2 H)1.35-1.52 (m, 4 H) 1.11 (d, J = 7.0 Hz, 3 H). LCMS-ESI (pos.) m/z: 583.0(M + H)⁺. 183.0 (Z)-N-(((1R,2S)-1-(5- chloropyrimidin-2-yl)-1-methoxypropan-2-yl)sulfonyl)-N′- (4,6-dimethoxypyrimidin-5-yl)hydrazinecarboximidamide (Example 161.2), spiro[2.3]hexane-5-carboxylic acid (commercially available from Enamine).

(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(spiro[2.3]hexan-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide. ¹H NMR (500 MHz,DMSO-d₆) δ 12.84-13.04 (m, 1 H) 8.89-9.03 (m, 2 H) 8.60-8.82 (m, 1 H)4.70-4.86 (m, 1 H) 3.94 (m, 6H) 3.37-3.45 (m, 1 H) 3.31-3.37 (m, 1 H)3.09-3.19 (m, 3 H) 2.38-2.44 (m, 2 H) 2.06- 2.15 (m, 2 H) 1.12-1.15 (m,3 H) 0.38-0.48 (m, 2 H) 0.29-0.38 (m, 2 H). LCMS-ESI (pos.) m/z: 551.2(M + H)⁺. 184.0 (Z)-N-(((1R,2S)-1-(5- chloropyrimidin-2-yl)-1-methoxypropan-2-yl)sulfonyl)-N′- (4,6-dimethoxypyrimidin-5-yl)hydrazinecarboximidamide (Example 161.2),spiro[3,3]heptane-2-carboxylic acid (commercially available fromEnamine).

(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(spiro[3.3]heptan-2-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide. ¹H NMR (500 MHz,DMSO-d₆) δ 12.82-13.07 (m, 1 H) 8.84-9.03 (m, 2 H) 8.63-8.84 (m, 1 H)4.66-4.86 (m, 1 H) 3.92-3.97 (m, 6 H) 3.36-3.44 (m, 1 H) 3.10- 3.16 (m,3 H) 3.01 (quin, J = 8.4 Hz, 1 H) 2.06-2.18 (m, 4 H) 1.92-1.98 (m, 2 H)1.80-1.89 (m, 2 H) 1.66- 1.75 (m, 2 H) 1.10-1.14 (m, 3 H). LCMS-ESI(pos.) m/z: 565.2 (M + H)⁺. 185.0 (Z)-N-(((1R,2S)-1-(5-chloropyrimidin-2-yl)-1- methoxypropan-2-yl)sulfonyl)-N′-(4,6-dimethoxypyrimidin-5- yl)hydrazinecarboximidamide (Example 161.2),and (1r,3r)-3- methylcyclobutane-1-carboxylic acid (commerciallyavailable from Synthonix).

(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(trans-3-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 12.82-13.03 (m, 1 H)8.86-8.98 (m, 2 H) 8.61-8.80 (m, 1 H) 4.65-4.86 (m, 1 H) 3.88-3.98 (m, 6H) 3.34-3.44 (m, 1 H) 3.16- 3.22 (m, 1 H) 3.11-3.15 (m, 3 H) 2.34-2.44(m, 1 H) 2.27-2.34 (m, 2 H) 1.66-1.76 (m, 2 H) 1.11-1.15 (m, 3 H)1.02-1.08 (m, 3 H). LCMS-ESI (pos.) m/z: 539.2 (M + H)⁺. 186.0(Z)-N-(((1R,2S)-1-(5- chloropyrimidin-2-yl)-1-methoxypropan-2-yl)sulfonyl)-N′- (4,6-dimethoxypyrimidin-5-yl)hydrazinecarboximidamide (Example 161.2), and (1s,3s)-3-methylcyclobutane-1-carboxylic acid (commercially available fromSynthonix).

(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(cis-3-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2- propanesulfonamide. ¹H NMR (500 MHz,DMSO-d₆) δ 12.77-12.97 (m, 1 H) 8.78-9.03 (m, 2 H) 8.68 (s, 1 H)4.66-4.86 (m, 1 H) 3.77-4.01 (m, 6 H) 3.39 (dd, J = 7.0, 4.0 Hz, 1 H)3.13 (s, 3 H) 2.89-3.03 (m, 1 H) 2.22-2.34 (m, 1 H) 2.09-2.19 (m, 2H)1.69-1.80 (m, 2 H) 1.11-1.16 (m, 3 H) 0.98 (d, J = 6.6 Hz, 3 H).LCMS-ESI (pos.) m/z: 539.2 (M + H)⁺. 195.0 (Z)-N-(((1R,2S)-1-(5-chloropyrimidin-2-yl)-1- methoxypropan-2-yl)sulfonyl)-N′- (2,6-dimethoxyphenyl)hydrazine- carboximidamide (Example 161.1), and3-fluoro-3-methylcyclobutane-1- carboxylic acid (commercially availablefrom Synthonix).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1s,3R)-3-fluoro-3-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1- methoxypropane-2-sulfonamideor (1R,2S)-1-(5- chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1r,3S)-3-fluoro-3-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d6) δ12.72-12.91 (m, 1 H) 8.79-8.99 (m, 2 H) 7.39-7.64 (m, 1 H) 6.72-6.99 (m,2 H) 4.71-4.87 (m, 1 H) 3.68-3.89 (m, 6 H) 3.36- 3.44 (m, 1 H) 3.14 (s,3 H) 3.02-3.11 (m, 1 H) 2.28- 2.40 (m, 4 H) 1.34-1.42 (m, 3 H) 1.13 (d,J = 7.0 Hz, 3 H). LCMS-ESI (pos.) m/z: 555.2 (M + H)⁺. 196.0(Z)-N-(((1R,2S)-1-(5- chloropyrimidin-2-yl)-1-methoxypropan-2-yl)sulfonyl)-N′- (2,6- dimethoxyphenyl)hydrazinecarboximidamide (Example 161.1), and2,2-dimethyl-3-oxocyclobutane-1- carboxylic acid (commercially availablefrom Synthonix).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((R)-2,2-dimethyl-3-oxocyclobutyl)-4H-1,2,4-triazol-3-yl)-1- methoxypropane-2-sulfonamide or(1R,2S)-1-(5- chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((S)-2,2-dimethyl-3-oxocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, CDCl₃) δ10.80-11.06 (m, 1 H) 8.71 (s, 2 H) 7.44 (t, J = 8.5 Hz, 1 H) 6.68 (d, J= 8.4 Hz, 2 H) 4.89-5.03 (m, 1 H) 3.86-3.93 (m, 1 H) 3.80-3.85 (m, 6 H)3.65-3.76 (m, 1 H) 3.29-3.38 (m, 3 H) 3.15- 3.23 (m, 1 H) 2.90 (t, J =8.8 Hz, 1 H) 1.35 (d, J = 7.0 Hz, 3 H) 0.99-1.03 (m, 3 H) 0.71 (s, 3 H).LCMS-ESI (pos.) m/z: 565.1 (M + H)⁺. 197.0 (Z)-N-(((1R,2S)-1-(5-chloropyrimidin-2-yl)-1- methoxypropan-2-yl)sulfonyl)-N′- (2,6-dimethoxyphenyl)hydrazine- carboximidamide (Example 161.1), and2,2-dimethyl-3-oxocyclobutane-1- carboxylic acid (commercially availablefrom Synthonix)

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((R)-2,2-dimethyl-3-oxocyclobutyl)-4H-1,2,4-triazol-3-yl)-1- methoxypropane-2-sulfonamide or(1R,2S)-1-(5- chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((S)-2,2-dimethyl-3-oxocyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ12.82-13.08 (m, 1 H) 8.85-9.05 (m, 2 H) 7.45-7.63 (m, 1 H) 6.78-6.95 (m,2 H) 4.77-4.90 (m, 1 H) 3.74-3.80 (m, 6 H) 3.66 (dd, J = 17.8, 8.4 Hz, 1H) 3.40 (br dd, J = 6.6, 4.2 Hz, 1 H) 3.25 (dd, J = 17.7, 9.1 Hz, 1 H)3.15 (s, 3 H) 2.95 (s, 1 H) 1.15 (d, J = 7.0 Hz, 3 H) 0.89 (s, 3 H) 0.61(s, 3 H). LCMS-ESI (pos.) m/z: 565.1 (M + H)⁺. 198.0(Z)-N-(((1R,2S)-1-(5- chloropyrimidin-2-yl)-1-methoxypropan-2-yl)sulfonyl)-N′- (2,6- dimethoxyphenyl)hydrazine-carboximidamide (Example 161.1), and 3-fluoro-3-methylcyclobutane-1-carboxylic acid (commercially available from Synthonix).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1s,3R)-3-fluoro-3-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1- methoxypropane-2-sulfonamideor ((1R,2S)-1-(5- chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((1r,3S)-3-fluoro-3-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ12.69-12.86 (m, 1 H) 8.84-9.07 (m, 2 H) 7.38-7.64 (m, 1 H) 6.84 (dd, J =8.6, 1.0 Hz, 2 H) 4.76 (d, J = 4.3 Hz, 1 H) 3.74 (m, 6 H) 3.39 (dd, J =7.0, 4.4 Hz, 1 H) 3.13-3.15 (m, 3 H) 2.36-2.47 (m, 2 H) 2.12-2.22 (m, 2H) 1.33-1.42 (m, 3 H) 1.13 (d, J = 7.0 Hz, 3 H). LCMS-ESI (pos.) m/z:555.2 (M + H)⁺. 199.0 (Z)-N-(((1R,2S)-1-(5- chloropyrimidin-2-yl)-1-methoxypropan-2-yl)sulfonyl)-N′- (2,6- dimethoxyphenyl)hydrazine-carboximidamide (Example 161.1), and 4-cyanocyclohexane-1-carboxylicacid (commercially available from Enamine).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1r,4R)-4-cyanocyclohexyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((1s,4R)-4-cyanocyclohexyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆)δ 12.73-12.91 (m, 1 H) 8.79-9.05 (m, 2 H) 7.51 (t, J = 8.5 Hz, 1 H) 6.86(dd, J = 8.6, 1.0 Hz, 2 H) 4.77 (d, J = 4.3 Hz, 1 H) 3.76 (m, 6 H)3.35-3.43 (m, 1 H) 3.14 (s, 3 H) 3.00-3.07 (m, 1 H) 2.19-2.28 (m, 1 H)1.81-1.89 (m, 2 H) 1.48- 1.71 (m, 6 H) 1.12 (d, J = 7.0 Hz, 3 H).LCMS-ESI (pos.) m/z: 576.2 (M + H)⁺. 203.0 (Z)-N-(((1R,2S)-1-(5-chloropyrimidin-2-yl)-1- methoxypropan-2-yl)sulfonyl)-N′-(4,6-dimethoxypyrimidin-5- yl)hydrazinecarboximidamide (Example 161.2),3,3- dichlorocyclobutane-1-carboxylic acid (commercially available fromSynthonix).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-(3,3-dichlorocyclobutyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide. ¹H NMR (500 MHz,DMSO-d6) δ 13.08-13.26 (m, 1 H) 8.93 (s, 2 H) 8.69 (s, 1 H) 4.76 (d, J =4.0 Hz, 1 H) 3.95 (m, 6 H) 3.53 (t, J = 8.5 Hz, 1 H) 3.35-3.44 (m, 1 H)3.19-3.24 (m, 4 H) 3.13 (s, 3 H) 1.13 (d, J = 7.0 Hz, 3 H). LCMS-ESI(pos.) m/z: 593.0 (M + H)⁺. 204.0 (Z)-N-(((1R,2S)-1-(5-chloropyrimidin-2-yl)-1- methoxypropan-2-yl)sulfonyl)-N′-(4,6-dimethoxypyrimidin-5- yl)hydra/,inecarboximidamide (Example 161.2),and 1,1- difluorospiro[2.3]hexane-5- carboxylic acid (commerciallyavailable from Enamine).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((3R,5s)-1,1-difluorospiro[2.3]hexan-5-yl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((3S,5r)-1,1-difluorospiro[2.3]hexan-5-yl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 12.89-13.16(m, 1 H) 8.87-9.04 (m, 2 H) 8.63-8.77 (m, 1 H) 4.68-4.85 (m, 1 H) 3.94(d, J = 4.9 Hz, 6 H) 3.36-3.47 (m, 2 H) 3.14 (s, 3 H) 2.39-2.45 (m, 2 H)2.28-2.38 (m, 2 H) 1.40 (t, J = 8.8 Hz, 2 H) 1.14 (d, J = 7.0 Hz, 3 H).LCMS- ESI (pos.) m/z: 587.1 (M + H)⁺. 205.0 (Z)-N-(((1R,2S)-1-(5-chloropyrimidin-2-yl)-1- methoxypropan-2-yl)sulfonyl)-N′-(4,6-dimethoxypyrimidin-5- yl)hydrazinecarboximidamide (Example 161.2),and 1,1- dilluorospiro[2.3]hexane-5- carboxylic acid (commerciallyavailable from Enamine).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((3R,5s)-1,1-difluorospiro[2.3]hexan-5-yl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(5-((3S,5r)-1,1-difluorospiro[2.3]hexan-5-yl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (600 MHz, DMSO-d₆) δ 12.36-13.02(m, 1 H) 8.87-9.03 (m, 1 H) 7.50 (t, J = 8.5 Hz, 1 H) 6.84 (dd, J = 8.6,1.7 Hz, 2 H) 4.69-4.82 (m, 1 H) 4.47-4.52 (m, 2 H) 4.41 (s, 2 H)3.71-3.80 (m, 6 H) 3.39 (qd, J = 6.9, 4.5 Hz, 1 H) 3.14 (s, 3 H)2.78-2.90 (m, 1 H) 2.31- 2.39 (m, 2 H) 2.27 (dtd, J = 12.0, 6.1, 6.1,2.8 Hz, 2 H) 1.09-1.16 (m, 3 H). LCMS-ESI (pos.) m/z: 565.2 (M + H)⁺.

The compounds set forth in the following table were synthesizedfollowing the procedure in Example 42.0 using the known startingmaterial as described.

TABLE 18 Example Reagents Structure, Name and Data 210.02-(5-chloropyrimidin-2- yl)ethanesulfonamide (Example 210.1),5-isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1), andcyclobutanecarbohydrazide ((commercially available from ChemBrigeCorporation)

2-(5-chloro-2-pyrimidin-yl)-N-(5-cyclobutyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3- yl)ethanesulfonamide. ¹H NMR (600MHz, DMSO-d₆) δ 12.91 (s, 1 H) 8.86 (s, 2 H) 7.49 (t, J = 8.49 Hz, 1 H)6.83 (d, J = 8.56 Hz, 2 H) 3.74 (s, 3 H) 3.74 (s, 3 H) 3.25-3.41 (m, 2H) 3.15- 3.21 (m, 2 H) 2.96-3.05 (m, 1 H) 2.10-2.21 (m, 2 H) 1.83-1.97(m, 3 H) 1.70-1.80 (m, 1 H). LCMS- ESI (pos.) m/z: 479.2 (M + H)⁺ 211.0(1S,2S)-1-(5-chloropyrimidin-2- yl)-1-isopropoxypropane-2- sulfonamide(Example 31.1), 4- isothiocyanatotetrahydro-2H-pyran ((commerciallyavailable from Enamine), and cyclobutanecarbohydrazide ((commerciallyavailable from ChemiBridge Corporation).

(1S,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-cyclobutyl-4-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)-1-(2-propanyloxy)-2-propanesulfonamide. ¹H NMR (600 MHz, DMSO-d₆) δ12.42 (s, 1 H) 8.95 (s, 2 H) 4.88-4.92 (m, 1 H) 3.98-4.06 (m, 1 H) 3.94(br d, J = 10.51 Hz, 2 H) 3.70 (quin, J = 8.35 Hz, 1 H) 3.50-3.56 (m, 1H) 3.35-3.43 (m, 3 H) 2.52 (m, 1 H) 2.29-2.37 (m, 2 H) 2.24 (quin, J =9.52 Hz, 2 H) 1.99-2.09 (m, 1 H) 1.82-1.90 (m, 1 H) 1.56 (br d, J =10.51 Hz, 2 H) 1.11 (d, J = 7.08 Hz, 3 H) 1.01 (d, J = 5.99 Hz, 3 H)0.79 (d, J = 6.07 Hz, 3 H). LCMS-ESI (pos.) m/z: 499.2 (M + H)⁺.

Example 210.1. Preparation of 2-(5-chloropyrimidin-2-yl)ethanesulfonamide

5-Chloro-2-vinylpyrimidine, Example 210.11

To a stirred solution of 2,5-dichloropyrimidine (Combi-blocks, 20 g, 134mmol, 1.0 equiv) in DMF (200 mL) was added tri-n-butyl(vinyl)stannane(Reddy & Reddy, 42.6 g, 134 mmol, 1.0 equiv) at RT. The reaction mixturewas degassed and purged with nitrogen for 5 mins. To the above reactionmixture was added Pd(PPh₃)₄ (4.65 g, 4.03 mmol, 0.03 equiv), and themixture was stirred at 100° C. for 16 h. The reaction mixture was cooledto RT, quenched with ice cold water (150 mL) and extracted with diethylether (2×300 mL). The combined organic layers were washed with brine(200 mL), dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to give Example 210.11 (50 g) as a yellow oil. This material wasutilized in the next step without further purification. LCMS-ESI (pos.)m/z: 141.3 (M+H)⁺.

2-(5-Chloro pyrimidin-2-yl)ethanesulfonic acid sodium salt, Example210.12

A solution of Example 210.11 (20 g, 142 mmol, 1.0 equiv) in a saturatedaqueous sodium bisulfite solution ((Spectrochem, 80 mL) was stirred atRT for 12 h. The reaction mixture was concentrated in vacuo and theresidue was purified by reverse phase flash chromatography (120 g, RediSep) eluting with 100% water to give Example 210.12 (17.5 g, 55% yield)as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (s, 2H), 3.16 (t,J=8.0 Hz, 2H), 2.85 (t, J=8.0 Hz, 2H). LCMS-ESI (pos.) m/z: 223.1(M+H)⁺.

2-(5-Chloropyrimidin-2-yl)-N-(4-methoxybenzyl)ethanesulfonamide, Example210.13

To a stirred solution of Example 210.12 (15.0 g, 67.4 mmol) in DCM (375mL) were added oxalyl chloride (17.69 mL, 202 mmol) and DMF (0.2 mL,catalytic) at 0° C. The reaction mixture was stirred at RT for 1 h andconcentrated in vacuo. The residue was azeotroped withcyclopentylmethylether (200 mL) to give the acid chloride (17 g, crude)which was dissolved in DCM (375 mL). 4-Methoxybenzylamine (27.7 g, 202mmol, 3.0 equiv) and TEA (34.1 g, 337 mmol, 5.0 equiv) were added at 0°C., and the mixture was stirred at RT for 12 h. The reaction mixture wasquenched with water (500 mL) and extracted with DCM (2×750 mL). Thecombined organic layers were washed with brine (500 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue wasabsorbed onto a plug of silica gel (60-120 mesh) and purified by flashchromatography through a Redi-Sep pre-packed silica gel column (120 g),eluting with a gradient of 55% to 60% EtOAc in hexanes, to give Example210.13 (7.0 g, 30% yield) as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 8.86 (s, 2H), 7.69 (t, J=6.4 Hz, 1H), 7.23 (d, J=8.4 Hz,2H), 6.86 (d, J=8.4 Hz, 2H), 4.08 (d, J=6.4 Hz, 2H), 3.71 (s, 3H), 3.39(t, J=6.8 Hz, 2H), 3.24 (t, J=6.8 Hz, 2H). LCMS-ESI (pos.) m/z: 342.1(M+H)⁺.

Synthesis of 2-(5-chloropyrimidin-2-yl) ethanesulfonamide, Example 210.1

To a stirred solution of Example 210.13 (16 g, 46.8 mmol, 1.0 equiv) inDCM (300 mL) was added TFA (220 mL, 2856 mmol) at 0° C., and the mixturewas stirred at room temperature for 16 h. The reaction mixture was thenconcentrated in vacuo. The residue was absorbed onto a plug of silicagel (60-120 mesh) and purified by flash chromatography through aRedi-Sep pre-packed silica gel (120 g) eluting with a gradient of 55% to70% EtOAc in hexanes to give Example 210.1 (8.0 g, 77% yield) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (s, 2H), 6.95 (s, 2H),3.47 (t, J=6.8 Hz, 2H), 3.33 (t, J=6.8 Hz, 2H). LCMS-ESI (pos.) m/z:222.0 (M+H)⁺.

Example 214.0: Preparation of(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1S,3S)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamideor(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,3R)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamideor(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,3S)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamideor(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1S,3R)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide

(Z)—N-(((1R,2S)-1-(5-Chloropyrimidin-2-yl)-1-methoxypropan-2-yl)sulfonyl)-N′-(2,6-dimethoxyphenyl)-2-((1S,3R)-3-methoxycyclopentanecarbonyl)hydrazinecarboximidamide and(Z)—N-(((1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropan-2-yl)sulfonyl)-N′-(2,6-dimethoxyphenyl)-2-((1R,3R)-3-methoxycyclopentanecarbonyl)hydrazinecarboximidamideand(Z)—N-(((1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropan-2-yl)sulfonyl)-N′-(2,6-dimethoxyphenyl)-2-((1S,3S)-3-methoxycyclopentanecarbonyl)hydrazinecarboximidamideand(Z)—N-(((1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropan-2-yl)sulfonyl)-N′-(2,6-dimethoxyphenyl)-2-((1R,3S)-3-methoxycyclopentanecarbonyl)hydrazinecarboximidamide,Example 214.2

To a vial containing 3-methoxycyclopentane-1-carboxylic acid(commercially available from Enamine, 167.3 mg, 1.16 mmol)) in EtOAc (3mL) was added diisopropylethylamine (0.3 mL, 1.8 mmol) and then1-propanephosphonic acid cyclic anhydride, (50 wt. % solution in EtOAc,T3P, 1.1 mL, 1.8 mmol) carefully dropwise at 23° C. After 30 minutes,Example 161.1 (406 mg, 0.82 mmol) was added in one portion at 23° C.After 19 h, the reaction was concentrated in vacuo. The residue was thenloaded onto a silica gel column (30-60% 3:1 EtOAc:EtOH in heptane).Fractions containing product were combined and then concentrated invacuo to afford Example 214.2 (360.2 mg, 0.68 mmol, 89% yield) as awhite foam that was used without further purification. LCMS-ESI (pos.),m/z: 585.0 (M+H)⁺.

(1R,2S)-1-(5-Chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1S,3S)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamideand(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,3R)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamideand(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,3S)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamideand(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1S,3R)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide,Example 214.3

To a vial containing Example 214.2. (293 mg, 0.50 mmol) in IPA (1.3 mL)and water (0.66 mL) was added sodium hydroxide (1N, 0.66 mL, 0.66 mmol)carefully dropwise to the reaction mixture. Upon complete addition, themixture was heated on a preheated stir plate at 80° C. After 1.5 h, thereaction was cooled to RT and then diluted with water. The pH wasadjusted with dropwise addition of 1 N aqueous citric acid solution topH-7. The reaction mixture was extracted three times with DCM. Theorganic layers were combined and then dried over anhydrous magnesiumsulfate. After filtration and concentration in vacuo, the residue wasloaded onto a silica gel column (40-90% 3:1 EtOAc:EtOH in heptane).Fractions containing product were combined and then concentrated invacuo to afford a white foam as Example 214.3. LCMS-ESI (pos.), m/z:567.2 (M+H)⁺.

The compounds set forth in the following table were synthesizedfollowing the procedure in Example 214.3 using the known startingmaterial as described.

TABLE 19 Example Reagents Structure, Name and Data 214.0 Example 214.3was purified by preparative SFC method: Column: OJ- H (2 × 25 cm) + OJ-H(2 × 15 cm), Mobile Phase: 80:20 (A:B) A: Liquid CO₂, B: IPA, Flow Rate:80 mL/min, 215 nm, 100 bar inlet pressure to deliver racemic Peak 1.Racemic peak 1 was further purified by preparative SFC method: Column:AD-H (2 × 25 cm) Mobile Phase: 60:40 (A:B) A: Liquid CO₂, B: IPA, FlowRate: 80 mL/min, 215 nm, 100 bar inlet pressure to deliver Peak 1.

(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1S,3S)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide or (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,3R)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide or(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,3S)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide or (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1S,3R)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide. ¹H NMR (400 MHz, CD₂Cl₂) δ10.68 (br s, 1H), 8.71 (s, 2H), 7.48 (t, J = 8.5 Hz, 1H) 6.72 (d, J =8.5 Hz, 2H), 4.85 (d, J = 4.6 Hz, 1H), 3.88-3.83 (m, 1H), 3.82-3.80 (m,3H), 3.80-3.79 (m, 3H), 3.60- 3.53 (m, 1H), 3.25 (s, 3H), 3.15 (s, 3H),2.84 (quin, J = 8.3 Hz, 1H), 1.96-1.72 (m, 5H), 1.66-1.61 (m, 1H), 1.25(d, J = 6.8 Hz, 3H). Mass Spectrum (pos.) m/e: 567.0 (M + H)⁺. LCMS-ESI(pos.), m/z: 567.0 (M + H)⁺. 215.0 Example 214.3 was purified bypreparative SFC method: Column: OJ- H (2 × 25 cm) + OJ-H (2 × 15 cm),Mobile Phase: 80:20 (A:B) A: Liquid CO₂, B: IPA, Flow Rate: 80 mL/min,215 nm, 100 bar inlet pressure to deliver racemic Peak 1. Racemic peak 1was further purified by preparative SFC method: Column: AD-H (2 × 25 cm)Mobile Phase: 60:40 (A:B) A: Liquid CO₂, B: IPA, Flow Rate: 80 mL/min,215 nm, 100 bar inlet pressure to deliver Peak 2

(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1S,3S)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide or (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,3R)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide or(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,3S)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide or (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1S,3R)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide. ¹H NMR (400 MHz, CD₂Cl₂) δ10.68 (br s, 1H), 8.71 (s, 2H), 7.48 (t, J = 8.5 Hz, 1H), 6.72 (d, J =8.5 Hz, 2H), 4.85 (d, J = 4.6 Hz, 1H), 3.87-3.83 (m, 1H), 3.83-3.81 (m,3H), 3.80-3.78 (m, 3H), 3.60- 3.53 (m, 1H), 3.24 (s, 3H), 3.15 (s, 3H),2.84 (quin, J = 8.2 Hz, 1H), 1.98-1.72 (m, 5H), 1.67-1.60 (m, 1H), 1.25(d, J = 7.0 Hz, 3H). LCMS-ESI (pos.). m/z: 567.0 (M + H)⁺. 216.0 Example214.3 was purified by preparative SFC method: Column: OJ- H (2 × 25cm) + OJ-H (2 × 15 cm), Mobile Phase: 80:20 (A:B) A: Liquid CO₂, B: IPA,Flow Rate: 80 mL/min, 215 nm, 100 bar inlet pressure to deliver racemicPeak 2.

(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1S,3S)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide and (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,3R)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide or(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,3S)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide and (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-((1S,3R)-3-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide. ¹H NMR (400 MHz, CD₂Cl₂) δ10.67 (br s, 1H), 8.71 (s, 2H), 7.48 (t, J = 8.5 Hz, 1H), 6.71 (d, J =8.5 Hz, 2H), 4.85 (d, J = 4.6 Hz, 1H), 3.83-3.80 (m, 3H), 3.80-3.77 (m,3H), 3.75-3.69 (m, 1H), 3.60- 3.53 (m, 1H), 3.25 (s, 3H), 3.23-3.20 (m,3H), 2.65 (quin, J = 8.6 Hz, 1H), 2.04-1.95 (m, 1H), 1.94- 1.82 (m, 2H),1.81-1.73 (m, 1H), 1.71-1.63 (m, 1H), 1.63-1.59 (m, 1H), 1.25 (d, J =7.0 Hz, 3H). LCMS-ESI (pos.), m/z: 567.0 (M + H)⁺. 217.0(Z)-N-(((1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropan-2-yl)sulfonyl)-N′- (2,6-dimethoxyphenyl)hydrazinecarboximida- mide (Example 161.1), andbicyclo[1.1.1]pentane-1-carboxylic acid (commercially available fromEnamine).

(1R,2S)-N-(5-bicyclo[1.1.1]pentan-1-yl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2- sulfonamdie. ¹H NMR (400 MHz,CD₂Cl₂) δ 11.30-10.38 (m, 1H), 8.71 (s, 2H), 7.48 (t, J = 8.6 Hz, 1H),6.70 (d, J = 8.7 Hz, 2H), 4.84 (d, J = 4.6 Hz, 1H), 3.81 (s, 3H), 3.79(s, 3H), 3.56 (dd, J = 4.8, 7.0 Hz, 1H), 3.25 (s, 3H), 2.32 (s, 1H),1.86 (m, 6H), 1.25 (d, J = 7.0 Hz, 3H). LCMS-ESI (pos.), m/z: 535.0 (M +H)⁺. 224.0 (Z)-N-(((1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropan-2-yl)sulfonyl)-N′- (2,6-dimethoxyphenyl)hydrazinecarboximida- mide (Example 161.1), and 3-oxo-1-cyclopentanecarboxylic (commercially available from Pharmablock Inc.).The racemic mixture was purified using the following preparative SFCmethod: Column: AS-H (2 × 25 cm) Mobile Phase: 60:40 (A:B) A: LiquidCO₂, B: MeOH, Flow Rate: 80 mL/min, 222 nm, 100 bar inlet pressure todeliver Peak 1.

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((R)-3-oxocyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)- N-(4-(2,6-dimethoxyphenyl)-5-((S)-3-oxocyclopentyl)-4H-1,2,4-triazol-3-yl)-1- methoxypropane-2-sulfonamide.¹H NMR (500 MHz, DMSO-d₆) δ 12.83 (br s, 1H), 8.93 (s, 2H), 7.52 (t, J =8.4 Hz, 1H), 6.87 (d, J = 8.6 Hz, 2H), 4.77 (d, J = 4.2 Hz, 1H),3.80-3.77 (m, 3H), 3.77-3.74 (m, 3H), 3.44-3.36 (m, 1H), 3.14 (s, 3H),3.10-3.04 (m, 1H), 2.32-2.26 (m, 1H), 2.26-2.19 (m, 1H), 2.18-2.12 (m,2H), 2.03-1.92 (m, 2H), 1.13 (d, J = 6.7 Hz, 3H). LCMS-ESI (pos.), m/z:551.2 (M + H)⁺. 225.0 (Z)-N-(((1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropan-2-yl)sulfonayl)-N′- (2,6-dimethoxyphenyl)hydrazinecarboximida- mide (Example 161.1), and 3-oxo-1-cyclopentaecarboxylic (commerically available from Pharmablock Inc.) Theracemic mixture was purified using the following preparative SFC method:Column: AS-H (2 × 25 cm) Mobile Phase: 60:40 (A:B) A: Liquid CO₂, B:MeOH, Flow Rate: 80 mL/min, 222 nm, 100 bar inlet pressure to deliverPeak 2.

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((R)-3-oxocyclopentyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2-yl)- N-(4-(2,6-dimethoxyphenyl)-5-((S)-3-oxocyclopentyl)-4H-1,2,4-triazol-3-yl)-1- methoxypropane-2-sulfonamide:¹H NMR (500 MHz, DMSO-d₆) δ = 12.83 (br s, 1H), 8.93 (s, 2H), 7.52 (t, J= 8.6 Hz, 1H), 6.88 (dd, J = 4.8, 8.4 Hz, 2H), 4.77 (d, J = 4.4 Hz, 1H),3.78- 3.76 (m, 6H), 3.40 (br dd, J = 4.5, 6.9 Hz, 1H), 3.14 (s, 3H),3.07 (quin, J = 7.8 Hz, 1H), 2.31-2.19 (m, 2H), 2.18-2.13 (m, 2H),2.01-1.92 (m, 2H), 1.13 (d, J = 7.0 Hz, 3H). LCMS-ESI (pos.), m/z: 551.2(M + H)⁺.

The compounds set forth in the following table were synthesizedfollowing the procedure in Example 42.0 using the known startingmaterial as described.

TABLE 20 Example Reagents Structure, Name and Data 218.0(2S,3R)-3-(5-chloropyrimidin-2- yl)butane-2-sulfonamide (Example 27.4),2-isothiocyanato-1,3- dimethoxybenzene (Example 28.0),(R)-spiro[2.2]pentane-1- carbohydrazide hydrochloride and (S)-spiro[2.2]pentane-1-carbohydrazide hydrochloride (Example 105.2). Theracemic mixture was purified using the following preparative SFC method:Column: AD-H (2 × 25 cm) Mobile Phase: 70:30 (A:B) A: Liquid CO₂, B:MeOH, Flow Rate: 80 mL/min, 215 nm, 100 bar inlet pressure to deliverPeak 1.

(2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((S)-spiro[2.2]pentan-1-yl)-4H-1,2,4-triazol-3-yl)butane-2-sulfonamide or(2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((R)-spiro[2.2]pentan-1-yl)-4H-1,2,4-triazol-3-yl)butane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ12.64 (br s, 1H), 8.85 (s, 2H), 7.49 (t, J = 8.6 Hz, 1H), 6.87- 6.80 (m,2H), 3.75 (s, 3H), 3.71 (s, 3H), 3.67- 3.62 (m, 1H), 3.55-3.50 (m, 1H),1.65 (dd, J = 4.7, 7.8 Hz, 1H), 1.47 (t, J = 4.3 Hz, 1H), 1.37 (dd, J =4.2, 7.8 Hz, 1H), 1.23 (d, J = 7.0 Hz, 3H), 1.10 (d, J = 7.0 Hz, 3H),0.84-0.78 (m, 1H), 0.77- 0.70 (m, 2H), 0.56-0.50 (m, 1H). LCMS-ESI(pos.) m/z: 591.2 (M + H)⁺. 219.0 (2S,3R)-3-(5-chloropyrimidin-2-yl)butane-2-sulfonamide (Example 27.4), 2-isothiocyanato-1,3-dimethoxybenzene (Example 28.0), and (R)-spiro[2.2]pentane-1-carbohydrazide hydrochloride and (S)- spiro[2.2]pentane-1-carbohydrazidehydrochloride (Example 105.2). The racemic mixture was purified usingthe following preparative SFC method: Column: AD-H (2 × 25 cm) MobilePhase: 70:30 (A:B) A: Liquid CO₂, B: MeOH, Flow Rate: 80 mL/min, 215 nm,100 bar inlet pressure to deliver Peak 2.

(2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((S)-spiro[2.2]pentan-1-yl)-4H-1,2,4-triazol-3-yl)butane-2-sulfonamide or(2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((R)-spiro[2.2]pentan-1-yl)-4H-1,2,4-triazol-3-yl)butane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ12.66 (s, 1H), 8.85 (s, 2H), 7.49 (t, J = 8.6 Hz, 1H), 6.84 (br d, J =8.6 Hz, 1H), 6.83-6.81 (m, 1H), 3.76 (s, 3H), 3.71 (s, 3H), 3.68-3.62(m, 1H), 3.56-3.50 (m, 1H), 1.64 (dd, J = 4.7, 7.8 Hz, 1H), 1.46 (t, J =4.4 Hz, 1H), 1.37 (dd, J = 4.2, 7.8 Hz, 1H), 1.23 (d, J = 7.0 Hz, 3H),1.10 (d, J = 7.0 Hz, 3H), 0.83- 0.78 (m, 1H), 0.78-0.73 (m, 2H),0.58-0.53 (m, 1H). LCMS-ESI (pos.) m/z: 519.2 (M + H)⁺. 220.0(2S,3R)-3-(5-chloropyrimidin-2- yl)butane-2-sulfonamide (Example 27.4),2-isothiocyanato-1,3- dimethoxybenzene, (Example 28.0), and (R)-2,2-difluorocyclopropanecarbohydrazide hydrochloride and (S)-2,2-difluorocyclopropanecarbohydrazide hydrochloride (Example 100.2). Theracemic mixture was purified using the following two preparative SFCmethods: Column: AS-H (2 × 25 cm) and AS-H (2 × 25 cm), Mobile Phase:80:20 (A:B) A: Liquid CO₂, B: MeOH, Flow Rate: 80 mL/min, 220 nm, 100bar inlet pressure to deliver Peak 1.

(2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(5-((R)-2,2-difluorocyclopropyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)butane- 2-sulfonamide or(2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(5-((S)-2,2-difluorocyclopropyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)butane- 2-sulfonamide. ¹H NMR(500 MHz, DMSO-d₆) δ 12.98 (br s, 1H), 8.85 (s, 2H), 7.52 (t, J = 8.6Hz, 1H), 6.87 (dd, J = 3.5, 8.4 Hz, 2H), 3.76 (s, 3H), 3.75-3.73 (m,3H), 3.69-3.63 (m, 1H), 3.59-3.53 (m, 1H), 2.55-2.50 (m, 1H), 2.03 (q, J= 9.3 Hz, 2H), 1.24 (d, J = 7.3 Hz, 3H), 1.12 (d, J = 7.0 Hz, 3H).LCMS-ESI (pos.) m/z: 529.2 (M + H)⁺. 221.0(2S,3R)-3-(5-chloropyrimidin-2- yl)butane-2-sulfonamide (Example 27.4),2-isothiocyanato-1,3- dimethoxybenzene (Example 28.0), and (R)-2,2-difluorocyclopropanecarbohydrazide hydrochloride and (S)-2,2-difluorocyclopropanecarbohydrazide hydrochloride (Example 100.2). Theracemic mixture was purified using the following preparative SFC method:Column: AS-H (2 × 25 cm) + AS-H (2 × 25 cm), Mobile Phase: 80:20 (A:B)A: Liquid CO₂, B: MeOH, Flow Rate: 80 mL/min, 220 nm, 100 bar inletpressure to deliver Peak 2.

(2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(5-((R)-2,2-difluorocyclopropyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)butane- 2-sulfonamide or(2S,3R)-3-(5-chloropyrimidin-2-yl)-N-(5-((S)-2,2-difluorocyclopropyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)butane- 2-sulfonamide. ¹H NMR(500 MHz, DMSO-d₆) δ 12.97 (br s, 1H), 8.86 (s, 2H), 7.52 (t, J = 8.6Hz, 1H), 6.87 (d, J = 8.6 Hz, 2H), 3.76 (s, 3H), 3.75-3.73 (m, 3H),3.68-3.62 (m, 1H), 3.58-3.52 (m, 1H), 2.55- 2.50 (m, 1H), 2.07-2.00 (m,2H), 1.24 (d, J = 7.0 Hz, 3H), 1.12 (d, J = 7.0 Hz, 3H). LCMS-ESI (pos.)m/z: 529.2 (M + H)⁺. 222.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2-sulfonamide (Example 29.3), 2-isothiocyanato-1,3-dimethoxybenzene (Example 28.0), and (R)-spiro[2.2]pentane-1-carbohydrazide hydrochloride and (S)- spiro[2.2]pentane-1-carbohydrazidehydrochloride (Example 105.2). The racemic mixture was purified usingthe following three preparative SFC methods: Column: AD-H (2 × 25 cm)and AD-H (2 × 25 cm) and AD-H (2 × 25 cm), Mobile Phase: 65:35 (A:B) A:Liquid CO₂, B: IPA, Flow Rate: 40 mL/min, 215 nm, 100 bar inlet pressureto deliver Peak 1.

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((S)-spiro[2.2]pentan-1-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2- yl)-N-(4-(2,6-dimethoxyphenyl)-5-((R)-spiro[2.2]pentan-1-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 12.66 (s, 1H),8.93 (s, 2H), 7.49 (t, J = 8.6 Hz, 1H), 6.84 (dd, J = 8.4, 16.5 Hz, 2H),4.78 (d, J = 4.2 Hz, 1H), 3.76 (s, 3H), 3.75-3.71 (m, 3H), 3.42-3.36 (m,1H), 3.14 (s, 3H), 1.66-1.63 (m, 1H), 1.48 (t, J = 4.3 Hz, 1H), 1.37(dd, J = 4.2, 8.0 Hz, 1H), 1.13 (d, J = 7.0 Hz, 3H), 0.83-0.78 (m, 1H),0.77-0.71 (m, 2H), 0.54 (dt, J = 3.9, 7.0 Hz, 1H). LCMS- ESI (pos.) m/z:535.1 (M + H)⁺. 223.0 (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2-sulfonamide (Example 29.3), 2-isothiocyanato-1,3-dimethoxybenzene (Example 28.0), and (R)-spiro[2.2]pentane-1-carbohydrazide hydrochloride and (S)- spiro[2.2]pentane-1-carbohydrazidehydrochloride (Example 105.2). The racemic mixture was purified usingthe following three preparative SFC method: Column: AD-H (2 × 25 cm) andAD-H (2 × 25 cm) and AD- H (2 × 25 cm), Mobile Phase: 65:35 (A:B) A:Liquid CO₂, B: IPA, Flow Rate: 40 mL/min, 215 nm, 100 bar inlet pressureto deliver Peak 2.

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-((S)-spiro[2.2]pentan-1-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2- sulfonamide or(1R,2S)-1-(5-chloropyrimidin-2- yl)-N-(4-(2,6-dimethoxyphenyl)-5-((R)-spiro[2.2]pentan-1-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 12.65 (s, 1H),8.93 (s, 2H), 7.49 (t, J = 8.6 Hz, 1H), 6.86-6.81 (m, 2H), 4.77 (d, J =4.4 Hz, 1H), 3.77 (s, 3H), 3.72 (s, 3H), 3.42-3.37 (m, 1H), 3.14 (s,3H), 1.65 (dd, J = 4.7, 8.0 Hz, 1H), 1.48 (t, J = 4.4 Hz, 1H), 1.37 (dd,J = 4.2, 8.0 Hz, 1H), 1.14 (d, J = 7.0 Hz, 3H), 0.84-0.78 (m, 1H),0.76-0.70 (m, 2H), 0.56-0.51 (m, 1H). LCMS-ESI (pos.) m/z: 535.1 (M +H)⁺.

Example 226.0: Preparation of(1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(trans-3-methoxycyclobutyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-1-(2-propanyloxy)-2-propanesulfonamideor(1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(cis-3-methoxycyclobutyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-1-(2-propanyloxy)-2-propanesulfonamide

(Z)—N′-(2,6-Dimethoxyphenyl)-N-(((1S,2S)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propan-2-yl)sulfonyl)hydrazinecarboximidamide,Example 226.1

The title compound was prepared in a similar manner to Example 161.1using Example 31.0 and Example 28.0. This afforded Example 226.1 as awhite solid. LCMS-ESI (pos.), m/z: 467.1 (M+H)⁺.

The compounds set forth in the following table were synthesizedfollowing the procedure in Example 214.3 using the known startingmaterial as described.

TABLE 21 Example Reagents Structure, Name and Data 226.0(Z)-N′-(2,6-dimethoxyphenyl)-N- (((1S,2S)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propan-2- yl)sulfonyl)hydrazinecarboximidamide(Example 226.1) and 3- methoxycyclobutanecarboxylic acid (commerciallyavailable from Pharmablock Inc.). The racemic mixture was purified usingthe following three preparative SFC methods: Column: AD—H (2 × 25 cm)and AD—H (2 × 25 cm) and AD—H (2 × 25 cm). Mobile Phase: 80:20 (A:B) A:Liquid CO₂. B: IPA. Flow Rate: 50 mL/min. 215 mn, 100 bar inlet

pressure to deliver Peak 1.

(1S,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(trans-3-methoxycyclobutyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-1-(2-propanyloxy)-2- propanesulfonamide or(1S,2S)-N-(4-(2,6- dimethoxyphenyl)-5-(cis-3-methoxycyclobutyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2- pyrimidinyl)-1-(2-propanyloxy)-2-propanesulfonamide. ¹H NMR (500 MHz, CD₂Cl₂) δ 8.63 (s, 2H), 7.45 (t, J= 8.4 Hz, 1H), 6.70 (t, J = 8.6 Hz, 2H), 4.81 (d, J = 4.4 Hz, 1H),4.04-3.99 (m, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.63-3.53 (m, 2H), 3.17(s, 3H), 3.05-2.98 (m, 1H), 2.63-2.57 (m, 1H), 2.46- 2.40 (m, 1H), 2.33(s, 3H), 2.14-2.02 (m, 2H), 1.34 (d, J = 7.0 Hz, 3H), 1.10 (d, J = 6.2Hz, 3H), 0.99 (d, J = 6.2 Hz, 3H). LCMS-ESI (pos.) m/z: 561.2 (M + H)⁺.227.0 (Z)-N′-(2,6-dimethoxyphcnyl)-N- (((1S,2S)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propan-2- yl)sulfonyl)hydrazinecarboximidamide(Example 226.1) and 3- methoxycyclobutanecarboxylic acid (commerciallyavailable from Pharmablock Inc.) The racemic mixture was purified usingthe following preparative SFC method: Column: AD—H (2 × 25 cm) + AD—H (2× 25 cm) + AD—H (2 × 25 cm), Mobile Phase: 80:20 (A:B) A: Liquid CO₂, B:IPA, Flow Rate: 50 mL/min, 215 nm, 100 bar inlet pressure to

deliver Peak 2.

(1S,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(trans-3-methoxycyclobutyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-1-(2-propanyloxy)-2- propanesulfonamide or(1S,2S)-N-(4-(2,6- dimethoxyphenyl)-5-(cis-3-methoxycyclobutyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2- pyrimidinyl)-1-(2-propanyloxy)-2-propanesulfonamide. ¹H NMR (500 MHz, CD₂Cl₂) δ 12.59-11.89 (m, 1H), 8.62(s, 2H), 7.46 (t, J = 8.4 Hz, 1H), 6.71 (t, J = 8.2 Hz, 2H), 4.80 (d, J= 4.4 Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.74-3.68 (m, 1H), 3.60- 3.51(m, 2H), 3.16 (s, 3H), 2.56 (tt, J = 7.8, 9.9 Hz, 1H), 2.40-2.34 (m,1H), 2.33 (s, 3H), 2.30- 2.24 (m, 1H), 2.23-2.17 (m, 1H), 2.12-2.05 (m,1H), 1.33 (d, J = 7.0 Hz, 3H), 1.09 (d, J = 6.0 Hz, 3H), 0.98 (d, J =6.2 Hz, 3H). LCMS-ESI (pos.) m/z: 561.2 (M + H)⁺. 228.0(Z)-N′-(2,6-dimethoxyphenyl)-N- (((1S,2S)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propan-2- yl)sulfonyl)hydrazinecarboximidamide(Example 226.1) and 3- hydroxybicyclo[1.1.1]pentane-1- carboxylic acid(commercially available from Pharmablock Inc.).

(1S,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(cis-4-hydroxybicyclo[1.1.1]pentan-2-yl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide and(1S,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(trans-4-hydroxybicyclo[1.1.1]pentan-2-yl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide. ¹H NMR (500 MHz, CD₂Cl₂) δ12.97-11.76 (m, 1H), 8.63-8.59 (m, 2H), 7.51-7.46 (m, 1H), 6.75-6.68 (m,2H), 4.79 (d, J = 4.2 Hz, 1H), 3.87- 3.84 (m, 3H), 3.82-3.78 (m, 3H),3.60-3.50 (m, 2H), 3.19-2.68 (m, 1H), 2.34-2.32 (m, 3H), 2.00-1.91 (m,6H), 1.34-1.30 (m, 3H), 1.10-1.07 (m, 3H), 0.98-0.94 (m, 3H). LCMS- ESI(pos.) m/z: 559.2 (M + H)⁺. 229.0 (Z)-N′-(2,6-dimethoxyphenyl)-N-(((1S,2S)-1-isopropoxy-1-(5- methylpyrimidin-2-yl)propan-2-yl)sulfonyl)hydrazinecarboximidamide (Example 226.1) and 3-oxo-1-cyclopentanecarboxylic (commercially available from Pharmablock Inc.)The racemic mixture was purifiedusing the following preparative SFCmethod: Column: AD—H (2 × 25 cm) Mobile Phase: 80:20 (A:B) A: LiquidCO₂, B: MeOH, Flow Rate: 100 mL/min, 220 mn, 100 bar inlet pressure todeliver Peak 1.

(1S,2S)-N-(4-(2,6-dimethoxyphenyl)-5-((R)-3-oxocyclopentyl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane- 2-sulfonamide or(1S,2S)-N-(4-(2,6- dimethoxyphenyl)-5-((S)-3-oxocyclopentyl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide. ¹H NMR (500 MHz, CD₂Cl₂) δ12.50 (br s, 1H), 8.63 (s, 2H), 7.52-7.47 (m, 1H), 6.78-6.71 (m, 2H),4.80 (d, J = 3.9 Hz, 1H), 3.91-3.87 (m, 2H), 3.83-3.80 (m, 3H),3.62-3.51 (m, 2H), 3.10- 3.04 (m, 1H), 2.58-2.50 (m, 1H), 2.37-2.30 (m,5H), 2.15-2.04 (m, 3H), 1.37 (d, J = 7.0 Hz, 3H), 1.09 (d, J = 6.0 Hz,3H), 0.96 (d, J = 6.2 Hz, 3H). LCMS-ESI (pos.) m/z: 559.3 (M + H)⁺.230.0 (Z)-N′-(2,6-dimethoxyphenyl)-N- (((1S,2S)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propan-2- yl)sulfonyl)hydrazinecarboximidamide(Example 226.1) and 3-oxo-1- cyclopentanecarboxylic (commerciallyavailable from Pharmablock Inc.). The racemic mixture was purified usingthe following preparative SFC method: Column: AD—H (2 × 25 cm) MobilePhase: 80:20 (A:B) A: Liquid CO₂, B: MeOH, Flow Rate: 100 mL/min, 220nm, 100 bar inlet pressure to deliver Peak 2.

(1S,2S)-N-(4-(2,6-dimethoxyphenyl)-5-((R)-3-oxocyclopentyl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane- 2-sulfonamide or(1S,2S)-N-(4-(2,6- dimethoxyphenyl)-5-((S)-3-oxocyclopentyl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide. ¹H NMR (500 MHz, CD₂Cl₂) δ12.71-12.29 (m, 1H), 8.63 (s, 2H), 7.49 (t, J = 8.6 Hz, 1H), 6.77- 6.72(m, 2H), 4.80 (d, J = 3.9 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.62-3.50(m, 2H), 3.09- 3.03 (m, 1H), 2.44-2.33 (m, 5H), 2.28-2.21 (m, 2H),2.20-2.11 (m, 2H), 1.36 (d, J = 7.0 Hz, 3H), 1.07 (d, J = 6.0 Hz, 3H),0.94 (d, J = 6.2 Hz, 3H). LCMS-ESI (pos.) m/z: 559.3 (M + H)⁺. 231.0(Z)-N′-(2,6-dimethoxyphenyl)-N- (((1S,2S)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propan-2- yl)sulfonyl)hydrazinecarboximidamide(Example 226.1) and 3-hydroxy-3- methylcyclobutanecarboxylic acid(commercially available from Pharmablock Inc.). The racemic mixture waspurified using the following preparative SFC method: Column: AS—H (2 ×15 cm). Mobile Phase: 75:25 (A:B) A: Liquid CO₂, B. EtOHl, Flow Rate:100 mL/min, 215 nm, 100 bar inlet pressure to deliver Peak 1.

(1S,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(trans-3-hydroxy-3-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-1-(2- propanyloxy)-2-propanesulfonamideor (1S,2S)- N-(4-(2,6-dimethoxyphenyl)-5-(cis-3-hydroxy-3-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-1-(2-propanyloxy)-2- propanesulfonamide. ¹H NMR(500 MHz, CD₂Cl₂) δ 12.60-11.91 (m, 1H), 8.62 (s, 2H), 7.46 (t, J = 8.6Hz, 1H), 6.71 (t, J = 8.3 Hz, 2H), 4.80 (d, J = 4.4 Hz, 1H), 3.84 (s,3H), 3.79 (s, 3H), 3.62-3.50 (m, 2H), 2.63- 2.53 (m, 1H), 2.42-2.28 (m,5H), 2.23-2.18 (m, 1H), 2.17-2.11 (m, 1H), 2.10-1.90 (m, 1H), 1.34-1.31(m, 3H), 1.27 (s, 3H), 1.08 (d, J = 6.2 Hz, 3H), 0.97 (d, J = 6.2 Hz,3H). LCMS-ESI (pos.) m/z: 561.2 (M + H)⁺. 232.0(Z)-N′-(2,6-dimethoxyphenyl)-N- (((1S,2S)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propan-2- yl)sulfonyl)hydrazinecarboximidamide(Example 226.1) and 3,3- difluorocyclopentanecarboxylic acid(commercially available from Synthonix).

(1S,2S)-N-(5-((1R)-3,3-difluorocyclopentyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-1-(2-propanyloxy)-2- propanesulfonamide and(1S,2S)-N-(5-((1S)-3,3- difluorocyclopentyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2- pyrimidinyl)-1-(2-propanyloxy)-2-propanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 12.81 (br s, 1H), 8.65(s, 2H), 7.52 (t, J = 8.4 Hz, 1H), 6.87 (d, J = 8.6 Hz, 2H), 4.69 (dd, J= 0.9, 7.4 Hz, 1H), 3.81 (s, 3H), 3.80-3.78 (m, 3H), 3.45-3.34 (m, 2H),2.96 (quin, J = 8.4 Hz, 1H), 2.34-2.19 (m, 5H), 2.19-2.03 (m, 2H),1.92-1.77 (m, 2H), 0.98 (d, J = 6.0 Hz, 3H), 0.91 (dd, J = 4.2, 7.0 Hz,3H), 0.79 (dd, J = 3.1, 6.2 Hz, 3H). LCMS-ESI (pos.) m/z: 581.3 (M +H)⁺. 233.0 (Z)-N′-(2,6-dimethoxyphenyl)-N- (((1S,2S)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propan-2- yl)sulfonyl)hydrazinecarboximidamide(Example 226.1) and 2- methoxycyclopentane-1-carboxylic acid(conunercially available from Enamine). The racemic mixture was purifiedusing the following preparative SFC method: Column: AD—H (2 × 25 cm) +AD—H (2 × 25 cm). Mobile Phase: 75:25 (A:B) A: Liquid CO₂, B: IPA, FlowRate: 60 mL/min, 215 nm, 100 bar inlet pressure to deliver fraction 1that was

resubjected to preparative SFC method: Column: AD—H (2 × 25 cm) + AD—H(2 × 25 cm). Mobile Phase: 80: 20 (A:B) A: Liquid CO₂, B: IPA. FlowRate: 60 mL/min, 215 nm, 100 bar inlet pressure to deliver Peak 1.

(1S,2S)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,2S)-2-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane- 2-sulfonamide or(1S,2S)-N-(4-(2,6- dimethoxyphenyl)-5-((1S,2R)-2-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane- 2-sulfonamide or(1S,2S)-N-(4-(2,6- dimethoxyphenyl)-5-((1R,2R)-2-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane- 2-sulfonamide or(1S,2S)-N-(4-(2,6- dimethoxyphenyl)-5-((1S,2S)-2-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane- 2-sulfonamide. ¹H NMR (500MHz, CD₂Cl₂) δ 12.32 (s, 1H), 8.64 (s, 2H), 7.48 (t, J = 8.6 Hz, 1H),6.73 (t, J = 8.7 Hz, 2H), 4.80 (d, J = 4.2 Hz, 1H), 3.94- 3.91 (m, 1H),3.87 (s, 3H), 3.81 (s, 3H), 3.63- 3.58 (m, 1H), 3.57-3.52 (m, 1H), 2.98(s, 3H), 2.71-2.66 (m, 1H), 2.34 (s, 3H), 1.91-1.82 (m, 3H), 1.80-1.73(m, 1H), 1.70-1.61 (m, 2H), 1.36 (d, J = 7.0 Hz, 3H), 1.09 (d, J = 6.0Hz, 3H), 0.98 (d, J = 6.2 Hz, 3H). LCMS-ESI (pos.) m/z: 575.2 (M + H)⁺.234.0 (Z)-N′-(2,6-dimethoxyphenyl)-N- (((1S,2S)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propan-2- yl)sulfonyl)hydrazinecarboximidamide(Example 226.1) and 2- methoxycyclopentane-1-carboxylic acid(commercially available from Enamine). The racemic mixture was purifiedusing the following two preparative SFC methods: Column: AD—H (2 × 25cm) + AD—H (2 × 25 cm). Mobile Phase: 75:25 (A:B) A: Liquid CO₂, B: IPA,Flow Rate: 60 mL/min, 215 nm, 100 bar inlet pressure to deliver fraction1 that was

resubjected to preparative SFC method: Column: AD—H (2 × 25 cm) + AD—H(2 × 25 cm), Mobile Phase: 80:20 (A:B) A: Liquid CO₂, B: IPA, Flow Rate:60 mL/min, 215 nm, 100 bar inlet pressure to deliver Peak 2.

(1S,2S)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,2 S)-2-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane- 2-sulfonamide or(1S,2S)-N-(4-(2,6- dimethoxyphenyl)-5-((1S,2R)-2-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane- 2-sulfonamide or(1S,2S)-N-(4-(2,6- dimethoxyphenyl)-5-((1R,2R)-2-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane- 2-sulfonamide or(1S,2S)-N-(4-(2,6- dimethoxyphenyl)-5-((1S,2S)-2-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane- 2-sulfonamide. ¹H NMR (500MHz, CD₂Cl₂) δ 12.28 (s, 1H), 8.63 (s, 2H), 7.48 (t, J = 8.4 Hz, 1H),6.73 (t, J = 8.2 Hz, 2H), 4.80 (d, J = 4.4 Hz, 1H), 4.13- 4.08 (m, 1H),3.88-3.84 (m, 3H), 3.83-3.80 (m, 3H), 3.62-3.56 (m, 1H), 3.56-3.50 (m,1H), 3.13-3.04 (m, 3H), 2.71-2.64 (m, 1H), 2.34 (s, 3H), 1.96-1.87 (m,1H), 1.84-1.78 (m, 1H), 1.72-1.62 (m, 4H), 1.34 (d, J = 7.0 Hz, 3H),1.08 (d, J = 6.0 Hz, 3H), 0.96 (d, J = 6.0 Hz, 3H). LCMS-ESI (pos.) m/z:575.2 (M + H)⁺. 235.0 (Z)-N′-(2,6-dimethoxyphenyl)-N-(((1S,2S)-1-isopropoxy-1-(5- methylpyrimidin-2-yl)propan-2-yl)sulfonyl)hydrazinecarboximidamide (Example 226.1) and 2-methoxycyclopentane-1-carboxylic acid (commercially available fromEnamine). The racemic mixture was purified using the follow ing twopreparative SFC methods: Column: AD—H (2 × 25 cm) + AD—H (2 × 25 cm).Mobile Phase: 75:25 (A:B) A: Liquid CO₂, B: IPA, Flow Rate: 60 mL/min,215 nm, 100 bar inlet pressure to deliver fraction 3.

(1S,2S)-N-(4-(2,6-dimethoxyphenyl)-5-((1R,2S)-2-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane- 2-sulfonamide or(1S,2S)-N-(4-(2,6- dimethoxyphenyl)-5-((1S,2R)-2-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane- 2-sulfonamide or(1S,2S)-N-(4-(2,6- dimethoxyphenyl)-5-((1R,2R)-2-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane- 2-sulfonamide or(1S,2S)-N-(4-(2,6- dimethoxyphenyl)-5-((1S,2S)-2-methoxycyclopentyl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane- 2-sulfonamide. ¹H NMR (500MHz, CD₂Cl₂) δ 12.19 (br s, 1H), 8.65-8.60 (m, 2H), 7.50-7.44 (m, 1H),6.73 (t, J = 9.0 Hz, 2H), 4.86-4.79 (m, 1H), 3.88-3.84 (m, 3H),3.84-3.81 (m, 3H), 3.61-3.51 (m, 2H), 3.37-3.31 (m, 1H), 3.11-3.01 (m,3H), 2.66-2.60 (m, 1H), 2.36-2.32 (m, 3H), 2.31- 2.21 (m, 1H), 1.94-1.78(m, 4H), 1.58-1.49 (m, 2H), 1.31-1.26 (m, 3H), 1.08 (d, J = 6.0 Hz, 3H),0.97 (d, J = 6.2 Hz, 3H). LCMS-ESI (pos.) m/z: 575.2 (M + H)⁺.

The compounds set forth in the following table were synthesizedfollowing the procedure in Example 42.0 using the known startingmaterial as described.

TABLE 22 Example Reagents Structure, Name and Data 236.0(1R,2S)-1-(5-chloropyrimidin-2-yl)- 1-methoxypropane-2-sulfonamide(Example 29.3), spiro[3.3]heptane-2- carbohydrazide (material wasprepared in an analogous maimer to that of Example 42.2 employing methylspiro[3.3]heptane-2- carboxylate (commercially available fromSigma-Aldrich Chemical Company) and heating at 80° C. for 5 hours), and2-isothiocyanato-1,3-

dimethoxybenzene (Example 28.0).(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(spiro[3.3]heptan-2-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2- propanesulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ 12.69 (s, 1H), 8.93 (s, 2H), 7.49 (t, J = 8.6 Hz, 1H), 6.83(d, J = 8.5 Hz, 2H), 4.76 (d, J = 4.4 Hz, 1H), 3.75 (s, 3 H), 3.73 (s, 3H), 3.39 (dd, J = 7.1, 4.5 Hz, 1 H), 3.14 (s, 3H), 2.82 (t, J = 8.5 Hz,1 H), 2.12 (br dd, J = 8.4, 3.6 Hz, 2 H), 2.05-1.96 (m, 2H), 1.96-1.87(m, 2H), 1.87-1.80 (m, 2H), 1.73-1.65 (m, 2H), 1.13 (d, J = 7.0 Hz, 3H). Mass Spectrum (pos.) m/z: 563.0 (M + H)⁺. 238.0(1R,2S)-1-(5-chloropyrimidin-2-yl)- 1-methoxypropane-2-sulfonamide,(Example 29.3), 3,3- dimethoxycyclobutanecarbohydrazide (Example 238.1),and 5- isothiocyanato-4,6- dimethoxypyrimidine (Example 28.1).

(1R,25)-1-(5-chloro-2-pyrimidinyl)-N-(5-(3,3-dimethoxycyclobutyl)-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2- propanesulfonamide. ¹HNMR (400 MHz, DMSO-d₆) δ 12.99 (s, 1H), 8.93 (s, 2H), 8.69 (s, 1H), 4.77(d, J = 4.1 Hz, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.40-3.35 (m, 1H), 3.13(s, 3H), 3.01 (m, 6H), 2.96-2.86 (m, 1H), 2.36-2.27 (m, 2H), 2.27-2.20(m, 2H), 1.14 (d, J = 7.1 Hz, 3H). Mass Spectrum (pos.) m/e: 585.0 (M +H)⁺.

The compounds set forth in the following table were synthesizedfollowing the procedure in Example 214.3 using the known startingmaterial as described.

TABLE 23 Example Reagents Structure, Name and Data 237.0(Z)-N-(((1R,2S)-1-(5- chloropyrimidin-2-yl)-1-methoxypropan-2-yl)sulfonyl)-N′- (2,6- dimethoxyphenyl)hydrazinecarboximidamide (Example 161.2), and 3-fluoro-3-methylcyclobutane-1- carboxylic acid (commercially availablefrom Synthonix Inc.).

(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1s,3S)-3-fluoro-3-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1- methoxypropane-2-sulfonamideor (1R,2S)-1-(5- chloropyrimidin-2-yl)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-((1r,3S)-3-fluoro-3-methylcyclobutyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ 13.02 (br s,1H), 8.93 (s, 2H), 8.69 (s, 1H), 4.78 (d, J = 4.1 Hz, 1H), 3.96 (s, 3H),3.94 (s, 3H), 3.40 (br s, 1H), 3.32- 3.23 (m, 1H), 3.13 (s, 3H),2.48-2.27 (m, 4H), 1.45 (d, J = 22.4 Hz, 3H), 1.13 (d, J = 7.0 Hz, 3H).Mass Spectrum (pos.) m/z: 557.0 (M + H)⁺. 239.0 (Z)-N′-(((1R,2S)-1-(5-chloropyrimidin-2-yl)-1- methoxypropan-2-yl)sulfonyl)- N′-(2,6-dimethoxyphenyl) hydrazinecarboximidamide (Example 161.1), andspiro[2.3]hexane-5-carboxylic acid (commercially available fromEnamine).

(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(spiro[2.3]hexan-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2- propanesulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ 12.74 (s, 1H), 8.93 (s, 2H), 7.49 (t, J = 8.5 Hz, 1H), 6.83(d, J = 8.5 Hz, 2H), 4.77 (d, J = 4.4 Hz, 1H), 3.74 (s, 3H), 3.73 (s,3H), 3.56-3.36 (m, 1H), 3.19-3.11 (m, 1H), 3.15 (s, 3H), 2.47-2.36 (m,2H), 2.04-1.95 (m, 2H), 1.14 (d, J = 6.8 Hz, 3H), 0.42-0.30 (m, 4H).Mass Spectrum (pos.) m/z: 549.2 (M + H)⁺.

Example 240.0: Preparation of(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(2-oxaspiro[3.3]heptan-6-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide

(1R,2S)-1-(5-Chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(2-oxaspiro[3.3]heptan-6-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide,Example 240.0

To a flask containing Example 161.2 (434 mg, 0.742 mmol) in water (3.7mL) was added potassium hydroxide (6M, 0.09 mL, 0.54 mmol) dropwise.Upon complete addition, the mixture was heated to 90° C. After 1 h, thereaction was cooled to RT and then diluted with water. The pH wascarefully adjusted to pH-7 by dropwise addition of 1 N aqueous citricacid solution. The mixture was then extracted three times with DCM. Theorganic layers were combined and then dried over anhydrous magnesiumsulfate. After filtration and concentration in vacuo, the residue wasloaded onto a silica gel column (25-70% 3:1 EtOAc:EtOH in heptane) toprovide Example 240.0 (421 mg, 0.354 mmol, 47.7%). ¹H NMR (400 MHz,DMSO-d₆) δ 12.94 (s, 1H), 8.93 (s, 2H), 8.69 (s, 1H), 4.76 (d, J=4.1 Hz,1H), 4.53 (s, 2H), 4.43 (s, 2H), 3.95 (s, 3H), 3.94 (s, 3H), 3.52-3.34(m, 1H), 3.34-3.25 (m, 1H), 3.13 (s, 3H), 3.03 (m, 1H), 2.34 (s, 3H),1.13 (d, J=7.0 Hz, 3H). Mass Spectrum (pos.) m/e: 567.0 (M+H)⁺.

The compounds set forth in the following table were synthesizedfollowing the procedure in Example 240.0 using the known startingmaterial as described.

TABLE 24 Example Reagents Structure, Name and Data 241.0cyclopentanecarbohydrazide (commercially available from MatrixScientific), (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5-cyclopentyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3- yl)-1-methoxy-2-propanesulfonamide(material was prepared in an analogous manner to that of Example 161.2employing 2-isothiocyanato-1,3- dimethoxybenzene (Example 28.0).

(1R,25)-1-(5-chloro-2-pyrimidinyl)-N-(5-cyclopentyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide. ¹H NMR (400 MHz, DMSO-d₆)δ 12.66 (s, 1H), 8.93 (s, 2H), 7.50 (t, J = 8.5 Hz, 1H), 6.85 (d, J =8.3 Hz, 2H), 4.76 (d, J = 4.4 Hz, 1H), 3.76 (s, 3H), 3.75 (s, 3H),3.43-3.34 (m, 1H), 3.14 (s, 3H), 2.57 (m, 1H), 1.70-1.54 (m, 6H), 1.53-1.41 (m, 2H), 1.13 (d, J = 7.0 Hz, 3H). Mass Spectrum (pos.) m/e: 537.1(M + H)⁺.

Biological Activity

[³⁵S]GTPγS Binding

The human APJ receptor was cloned by polymerase chain reaction and thegene encoding the receptor was subcloned in pFLAG-CMV™-3 expressionvector (Sigma, Saint Louis, Mo. USA) in-house at Amgen. A GTPγS bindingassay was performed on membranes prepared from CHO cells stablyexpressing human APJ receptor. The optimum experimental conditions forthe concentrations of GDP, MgCl₂, and NaCl in the assay buffer wereinitially determined. The assay was performed in 9 μL assay buffer [20mM HEPES, pH 7.5, 5 mM MgCl₂, 100 mM NaCl and 0.1% (w/v) BSA], 1 μL ofdiluted test compound (starting with 0.75 mM, 2-fold serial dilutionwith DMSO, total 22 points), 10 μL of 18 μM GDP (final concentration of3 μM GDP), 20 μL of 0.25 μg/mL membrane protein expressing human APJreceptor captured with WGA PS beads (final concentration of 5 μg perwell), and 20 μL of 0.3 nM [³⁵S]GTPγS (final concentration is 0.1 nM[³⁵S]GTPγS)(Perkin Elmer Life and Analytical Sciences, Waltham USA). Onecolumn of the plate was 1 μL of DMSO as background and another column ofthe plate was 1 μL of 180 μM Pyr-Apelin-13 which was used as control ata final concentration of 3 μM. Incubation was at RT for 90 min and themicroplate was read using a ViewLux™ ultra HTS Microplate Imager(PerkinElmer, Inc.). All the results presented are means of severalindependent experiments and analyzed by non-linear regression methodsusing the commercially available program Prism (GraphPad, San Diego,Calif.) providing the EC₅₀ values detailed in Table 25.

Evidence for Load Independent Inotropic Effects with APJ Agonists UsingEx Vivo Assay (Isolated Perfused Rat Hearts)

Naive Sprague Dawley® SD rats (Harlan laboratories (Livermore, Calif.USA)) were anaesthetized and hearts were excised followed by cannulationin the Langendorff apparatus (Harvard apparatus, Holliston, Mass. USA)via aorta. The heart was perfused retrograde with modified oxygenatedKrebs-Henseleit buffer (Skrzypiec-Spring M et al., (2007) J. PharmacolToxicol Methods 55: 113-126). The pressure of the solution causes theaortic valve to shut and the perfusate is then forced into the ostiumand the coronary vessels. This allows the heart to beat for severalhours. A balloon was inserted into the left ventricle (LV) to measuredP/dt_(max) (derivative of left ventricular pressure) as an index ofcardiac contractility. The APJ agonist was perfused constantly in a dosedependent manner into the heart to examine cardiac contractility.Administration of APJ agonist showed a dose-dependent increase ininotropic and lusitropic effects at varying degrees (Table 26). APJagonists of the present invention showed improvement in cardiaccontractility and relaxation when perfused into the heart as describedabove.

Evidence for Improvement in Cardiac Contractility In Vivo in HeartFailure Rat Model

Based on the ex vivo findings in isolated heart assay, APJ agonists maybe dosed in vivo to investigate the translation of cardiac contractilityin in vivo settings. Male Lewis rats (Charles River, USA) at 2-3 monthsof age are used for the study. Heart failure is induced by permanentligation of the left descending coronary artery which results in injuryto the heart with an ejection fraction of <35%. APJ agonists areadministered dose dependently acutely for a period of 30 min.Administration of example compounds will be found to lead to an increasein cardiac contractility as measured by dP/dt_(ma) (derivative of leftventricular pressure).

The following table includes biological activity data obtained using theprocedures and assays set forth above for the Example compoundsdescribed herein.

TABLE 25 Biological Activity Information for Example Compounds. ExampleActivity hAPJ SPA EC₅₀ IP (μM) 1.0 — 2.0 — 3.0 0.056 4.0 0.021 5.00.0094 6.0 0.0075 7.0 0.066 8.0 — 9.0 — 10.0 — 11.0 — 12.0 — 13.0 — 14.0— 15.0 — 16.0 0.022 17.0 0.0011 18.0 0.0021 19.0 0.0011 20.0 0.84 21.00.48 22.0 0.00029 23.0 0.014 24.0 0.011 25.0 0.027 26.0 0.0044 42.00.00040 43.0 Prophetic 44.0 Prophetic 45.0 Prophetic 46.0 Prophetic 47.0Prophetic 48.0 Prophetic 49.0 Prophetic 54.0 Prophetic 55.0 Prophetic56.0 Prophetic 57.0 Prophetic 58.0 This compound has been prepared (seeExample 179.0, Example 180.0, Example 181.0, and Example 182.0) 59.0Prophetic 60.0 Prophetic 61.0 Prophetic 62.0 Prophetic 63.0 Prophetic64.0 This compound has been prepared (see Example 146.0) 65.0 Prophetic66.0 Prophetic 67.0 Prophetic 68.0 Prophetic 69.0 Prophetic 70.0Prophetic 71.0 Prophetic 72.0 Prophetic 73.0 Prophetic 74.0 Prophetic75.0 Prophetic 76.0 Prophetic 77.0 Prophetic 78.0 Prophetic 79.0Prophetic 80.0 Prophetic 81.0 Prophetic 82.0 0.050 83.0 0.0060 84.00.0108 85.0 0.0017 86.0 0.036 87.0 0.0020 88.0 0.042 89.0 0.00074 90.00.0092 91.0 0.0029 92.0 0.0057 93.0 0.00091 94.0 0.00072 95.0 0.043 96.00.030 97.0 0.37 98.0 Prophetic 99.0 Prophetic 100.0 0.14 101.0 0.060102.0 0.16 103.0 0.039 105.0 0.00092 106.0 0.019 107.0 — 108.0 — 109.0 —110.0 — 111.0 Prophetic 112.0 Prophetic 118.0 0.0010 119.0 0.00079 120.00.0031 121.0 0.0054 122.0 0.028 123.0 0.0051 124.0 0.049 125.0 0.40126.0 4.20 127.0 — 128.0 0.33 129.0 — 130.0 1.50 131.0 0.11 132.0 1.27133.0 0.12 134.0 1.33 135.0 1.81 136.0 3.2 137.0 0.34 138.0 0.027 139.00.029 140.0 0.031 141.0 0.033 142.0 0.0051 143.0 0.0041 144.0 0.62 145.00.0048 146.0 0.026 147.0 0.0064 148.0 0.0011 149.0 0.0042 150.0 0.0068151.0 0.0054 152.0 0.0042 153.0 0.0015 154.0 0.00018 155.0 0.0094 156.00.011 159.0 0.0080 160.0 0.027 161.0 0.019 162.0 0.0140 163.0 0.046164.0 0.00054 165.0 0.0097 166.0 0.020 167.0 0.013 168.0 0.0080 169.00.021 170.0 0.018 172.0 0.37 173.0 0.013 174.0 1.2 175.0 0.059 176.00.017 177.0 0.023 178.0 0.0065 179.0 0.046 180.0 0.024 181.0 0.032 182.00.010 183.0 0.0014 184.0 0.0011 185.0 0.0027 186.0 0.00089 187.0 0.0088188.0 0.014 191.0 0.0075 192.0 0.0029 193.0 0.010 194.0 0.0025 195.00.0026 196.0 0.33 197.0 0.87 198.0 0.0037 199.0 0.0081 200.0 0.0046201.0 0.011 202.0 0.0042 203.0 0.010 204.0 0.034 205.0 0.0055 208.00.0027 209.0 0.018 210.0 0.015 211.0 0.42 214.0 0.020 215.0 0.066 216.00.015 217.0 0.0074 218.0 0.0011 219.0 0.029 220.0 0.039 221.0 0.018222.0 0.024 223.0 0.0012 224.0 0.038 225.0 0.16 226.0 0.021 227.0 0.0027228.0 0.19 229.0 0.030 230.0 0.19 231.0 0.22 232.0 0.042 233.0 0.094234.0 0.012 235.0 0.15 236.0 0.00099 237.0 0.030 238.0 0.12 239.00.00064 240.0 0.071 241.0 0.0012

The following table includes data obtained using the procedures andassays set forth above for the Example compounds described herein.

TABLE 26 Contractile Effects of Examples Observed in ex vivo (IsolatedHeart Assay) and in vivo (MI Rat Model). Isolated Heart Assay MI RatModel Example(s) dP/dt_(max) (%) dP/dt_(min) (%) dP/dt_(max) (%) 7 18.815.7 nd* 19 2.81 4.74 nd* *nd is not determined.

APJ is a G-protein coupled receptor that is closely related to theAngiotensin II Type 1 receptor (AT1R) with 50% homology in thetransmembrane domain. Apelin is a known endogenous ligand for APJ andrecently another ligand named ELABELA has been identified as anotherpotential ligand for the APJ receptor (Tatemoto, K. et al., Biochem.Biophys. Res. Commun., 251, pp. 471-476 (1998); Pauli, A. et al.,Science, 343, pp. 1248636 (2014)). Since its discovery, there isaccumulating evidence indicating the role of the apelin-APJ receptor inthe pathophysiology of cardiovascular diseases. Pre-clinical andclinical studies have shown that acute infusion of apelin or APJagonists improve cardiac function under heart failure settings (Berry,M. F., et al., Circulation, 110(11) pp. 11187-11193 (2004); Japp, A. G.et al., Circulation, 121, pp. 1818-1827 (2010)).

A key emerging aspect of the apelin-APJ system is its interaction withthe renin-angiotensin system. Apelin is also known to counter-regulatethe vasoconstriction actions of AngII. Apelin knockout mice show astrong increased vasopressor response to AngII indicating that theapelin/APJ system exerts the hypotensive effect in vivo against thepressor action of AngII. In addition, the apelin activated APJ pathwayinhibited angiotensin-mediated formation of atherosclerosis throughinteraction with the AT1R (Chun, H. J., et al., J. Clin. Invest., 118,pp. 3343-3354 (2008), Siddiquee, K. et al., J. Hypertens., 29, pp.724-731 (2011), Sun, X. et al., Hypertens. Res., 34, pp. 701-706(2011)). This could be mediated by convergence of two independentintracellular signaling pathways or via direct physical interaction ofAPJ with AT1R to form a heterodimer. Siddiquee et al. showed that theAngII signaling is antagonized through apelin-dependentheterodimerization and APJ mediated negative allosteric modulation ofAT1R function (Siddiquee, K. et al., Br. J. Pharmacol., 168, pp.1104-1117 (2013).

We were interested to understand if the heterodimerization of APJ-AT1Rupon activation by APJ agonists would have any beneficial outcomeclinically in heart failure patients considering most of these patientsare on standard of care drugs such as angiotensin blockers (angiotensinII receptor antagonists or angiotensin receptor blockers (ARBs)) andangiotensin converting enzyme (ACE) inhibitors. In order to explore thecross-talk between APJ and the AT1R receptor, we examined IP1 signalingmediated by AT1R upon activation with APJ agonists. Surprisingly andcontrary to the findings by Siddique et al., activation of the APJpathway resulted in positive cooperativity of AngII by shifting itspotency to the left and also increasing the efficacy of the IP response(see methods and results section below). Conversely, blocking the AT1Rreceptor by an ARB such as losartan relieved the inhibition of the APJreceptor and up regulates its signaling which is observed as synergisticeffects in both ex-vivo and in vivo studies. This work establishes a newparadigm for cross-talk interaction/heterodimerization between APJ &AT1R which might have implications for approaches to pharmacologicalinterventions in heart failure populations.

The interaction between acetyl cholinesterase (ACE2) and Apelin biologyis complicated. To investigate the interaction between the Apelin-APJand ACE signalling pathways, we examined the improvement in cardiacfunction with APJ small molecule agonists in the presence of ACEinhibitor captopril in heart failure rats in vivo. Captopril alone,under acute settings, does not show a marked improvement incontractility or ejection fraction acutely. However, in the presence ofan APJ agonist, there was a shift in potency to the left with markedimprovement in contractility and ejection fraction without changes inheart rate. These findings provide a new reference for the understandingof the regulation of ACE2 for the renin angiotensin aldosterone system(RAAS), independent of AT1R signaling and offer new potential drugtargets for the treatment of diseases such as hypertension and heartfailure. This work clearly establishes that combination of an agonist ofthe APJ receptor with an ARB such as losartan and/or with an ACEinhibitor such as captopril which may play an important role inproviding greater efficacy in treating heart failure patients, forexample in improving contractility and ejection fraction withoutchanging the heart rate.

Evidence for Allosteric Interaction Between APJ and AT1R Using IP Assay

Methods

Single and double stable recombinant cell lines were generated for humanAPJ and the AT1R receptor in CHO K1 cells tagged either with FLAG orhemagglutinin (HA) tag. Briefly, the CHO-K1 APJ/AT1R cells were seededin culture medium of DMEM-F12 and 10% FBS at a density of 15 k/well in a96 well plate overnight. The next day, the culture medium was replacedwith medium containing no serum for 4 hours. The compound AngII at arange of concentrations (1 pM-10 μM) with or without differentconcentrations of APJ agonists were diluted in stimulation buffer andadded to the cell plate. The plate was sealed and incubated for 1 hour.This was followed by addition of IP-d2 conjugate followed by europiumcryptate antibody conjugate into the wells. The plate was sealed,followed with incubation for 2 hours at RT. Time-resolved fluorescenceresonance energy (TR-FRET) at 620 nm and 665 nm was measured after 2hours with an Envision reader. The signal ratios and delta F werecalculated and the amount of IP1 produced was inversely proportional tothe TR-FRET ratio, 665/620 nm.

Results

In cells expressing both APJ and the AT1R receptor, addition of APJagonists at different concentrations increased the maximal response ofAngII and also shifted the potency to the left. The increase in IP1response reached a maximal effect both in potency and Emax indicating aceiling effect which is a hallmark for allosteric cooperativity betweenthe AT1R and APJ receptor (FIG. 1). However, this effect ofcooperativity was not observed in either APJ or AT1R recombinant stablecell lines indicating that there is functional cross-talk between thetwo receptors through physical interaction or with downstream effectors(FIG. 2 and FIG. 3). Based on the above findings of cooperativity, werationalized that if an APJ agonist can induce heterodimerization of APJwith AT1R, blocking the AT1R with losartan would enhance the activationof APJ upon addition of small molecule agonists. We observed that APJsmall molecule agonists induced positive cooperativity in the presenceof AngII and addition of losartan relieved this cooperativity andresulted in synergistic effects of enhancing the efficacy of the APJreceptor. This work clearly establishes that combination of an agonistof the APJ receptor with an ARB such as losartan or an ACE inhibitorsuch as captopril may play an important role in providing greaterefficacy in treatment of heart failure patients.

All publications and patent applications cited in this specification arehereby incorporated by reference herein in their entireties and for allpurposes as if each individual publication or patent application werespecifically and individually indicated as being incorporated byreference and as if each reference was fully set forth in its entirety.Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be readily apparent to those of ordinary skill inthe art in light of the teachings of this invention that certain changesand modifications may be made thereto without departing from the spiritor scope of the appended claims.

1. A compound of Formula I or Formula II:

or a pharmaceutically acceptable salt thereof, a tautomer thereof, apharmaceutically acceptable salt of the tautomer, a stereoisomer of anyof the foregoing, or a mixture thereof, wherein: R¹ is an unsubstitutedmonocyclic C₃-C₈ cycloalkyl, an unsubstituted C₅-C₈ polycycliccycloalkyl, an unsubstituted monocyclic C₄-C₈ cycloalkenyl, a monocyclicC₃-C₈ cycloalkyl substituted with 1, 2, 3, or 4 R^(1a) substituents, aC₅-C₈ polycyclic cycloalkyl substituted with 1, 2, or 3 R^(1a)substituents, or a monocyclic C₄-C₈ cycloalkenyl substituted with 1, 2,or 3 R^(1a) substituents; R^(1a) in each instance is independentlyselected from —F, —Cl, —Br, —I, —CN, —OH, ═O, —O—(C₁-C₆ alkyl),—O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₁-C₆ alkyl, —C₁-C₆haloalkyl, —C₁-C₆ perhaloalkyl, —C₂-C₄ alkenyl, ═CH₂, ═CH—(C₁-C₆ alkyl),—(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆haloalkyl)-OH, —(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆perhaloalkyl)-OH, —(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂,—NHS(═O)₂—(C₁-C₆ alkyl), —S(═O)₂—(C₁-C₆ alkyl), a phenyl group, or amonocyclic heteroaryl group with 5 or 6 ring members containing 1, 2, or3 heteroatoms independently selected from N, O, or S, wherein the R^(1a)phenyl and R^(1a) heteroaryl groups are unsubstituted or are substitutedwith 1, 2, or 3, R^(1a′) substituents; and further wherein two R^(1a)groups on a single carbon atom of a monocyclic C₃-C₈ cycloalkyl R¹ groupmay join together with the carbon atom to which they are attached toform a heterocyclic ring having 3 to 6 members of which 1 or 2 areheteroatoms independently selected from O, N, and S; R^(1a′) is in eachinstance, independently selected from —F, —Cl, —Br, —I, —CN, —OH,O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₁-C₆alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —C₂-C₄ alkenyl, —(C₁-C₆alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)-OH,—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ perhaloalkyl)-OH, —(C₁-C₆perhaloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,—C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂,—C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —NHS(═O)₂—(C₁-C₆ alkyl),or —S(═O)₂₋(C₁-C₆ alkyl); R² is selected from —H, or C₁-C₄ alkyl or isabsent in the compounds of Formula II; R³ is selected from a group offormula —(CR^(3b)R^(3c))-Q, a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q, a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—C(═O)-Q a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—CH(OH)-Q, a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—(CR^(3f)R^(3g))-Q, a group of formula—(C₃-C₈ cycloalkyl)-Q, or a group of formula -(heterocyclyl)-Q, whereinthe heterocyclyl of the -(heterocyclyl)-Q group has 5 to 7 ring membersof which 1, 2, or 3 are heteroatoms independently selected from N, O, orS and is unsubstituted or is substituted with 1, 2, or 3 R^(3h)substituents, and further wherein the C₃-C₈ cycloalkyl of the —(C₃-C₈cycloalkyl)-Q group is unsubstituted or is substituted with 1 or 2R^(3h) substituents; R^(3b) and R^(3c) are independently selected from—H, —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl,—OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl),—O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆alkyl), or —N(C₁-C₆ alkyl)₂; R^(3d) and R^(3e) are independentlyselected from —H, —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆perhaloalkyl, —OH, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl),—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl)-phenyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;R^(3f) and R^(3g) are independently selected from —H, —F, —Cl, —CN,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₂-C₆ alkenyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or—N(C₁-C₆ alkyl)₂; R^(3h) in each instance is independently selected from—F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH,—O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl),—O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)—(C₃-C₆cycloalkyl), —C(═O)—O—(C₁-C₆ alkyl), oxo, or —C(═O)-(heterocyclyl),wherein the heterocyclyl group of the R^(h)—C(═O)-(heterocyclyl) has 5or 6 ring members of which 1 or 2 are heteroatoms independently selectedfrom N, or S or has 3 or 4 ring members of which 1 is a heteroatomselected from N, O, or S; Q is a monocyclic or bicyclic C₆-C₀₀ arylgroup, a monocyclic or bicyclic heteroaryl group with 5 to 10 ringmembers containing 1, 2, or 3 heteroatoms independently selected from N,O, or S, a C₃-C₈ cycloalkyl group, a 3 to 10 membered heterocyclyl groupcontaining 1, 2, or 3 heteroatoms independently selected from N, O, orS, wherein the C₆-C₁₀ aryl, the heteroaryl, the cycloalkyl, and theheterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3,or 4 R^(Q) substituents; and further wherein the Q heterocyclyl groupmay additionally be substituted with 1 or 2 oxo substituents, and the Qheteroaryl group may include an N-oxide if the heteroaryl includes a Nheteroatom; R^(Q) in each instance is independently selected from —F,—Cl, —Br, —I, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl,—C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)₂, —NHC(═O)(C₁-C₆ alkyl), —C(═O)—(C₁-C₆ alkyl), —C(═O)OH,—C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆alkyl)₂, —S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-OH, —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-NH₂, —(C₁-C₆ alkyl)-NH—(C₁-C₆alkyl), —(C₁-C₆ alkyl)-N—(C₁-C₆ alkyl)₂, phenyl, a heterocyclyl group, a—(C₁-C₆ alkyl)heterocyclyl group, or a heteroaryl group with 5 or 6 ringmembers and 1, 2, or 3, heteroatoms independently selected from N, O, orS, wherein the heterocyclyl groups of the R^(Q) heterocyclyl and —(C₁-C₆alkyl)heterocyclyl groups have 3 to 6 ring members of which 1 or 2 areheteroatoms independently selected from N, O, or S, and further whereinthe heterocyclyl and the heterocyclyl of the —(C₁-C₆ alkyl)heterocyclylR^(Q) groups may be further substituted with one or two oxo substituentsand a substituent selected from —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₆alkyl, or —C(═O)—(C₁-C₆ alkyl); R⁴ is selected from a monocyclic orbicyclic C₆-C₁₀ aryl group, a monocyclic or bicyclic heteroaryl groupwith 5 to 10 ring members containing 1, 2, or 3 heteroatomsindependently selected from N, O, or S, a monocyclic or bicyclicheterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4heteroatoms independently selected from N, O, or S, a monocyclic 3-6membered cycloalkyl group, or a straight or branched chain C₁-C₆ alkylgroup, wherein the C₆-C₁₀ aryl, the heteroaryl, the heterocyclyl, andthe cycloalkyl R⁴ group are unsubstituted or are substituted with 1, 2,3, or 4 R^(4a) substituents, and further wherein the straight orbranched chain C₁-C₆ alkyl R⁴ group is unsubstituted or is substitutedwith 1, 2, or 3 R^(4b) substituents; R^(4a) in each instance isindependently selected from —F, —Cl, —Br, —I, —CN, —C₁-C₆ alkyl, —C₁-C₆haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl),—O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,NH(C₁-C₆ alkyl-OH), —N(C₁-C₆ alkyl-OH)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH,—C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆alkyl)₂, phenyl, —S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-heterocyclyl, orheterocyclyl wherein the heterocyclyl of the —(C₁-C₆ alkyl)-heterocyclyland heterocyclyl R^(4a) groups is a 3-6 membered ring comprising 1 or 2heteroatoms independently selected from N, O, or S, and is unsaturatedor partially unsaturated and is optionally substituted with 1 or 2 oxosubstituents, and further wherein the heterocyclyl of the R⁴ group maybe further substituted with 1 oxo substituent; and R^(4b) in eachinstance is selected from —F, —Cl, —Br, —I, —CN, —OH, —O—(C₁-C₆ alkyl),—O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆ alkyl-OH)₂, —C(═O)—(C₁-C₆alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆alkyl), —C(═O)N(C₁-C₆ alkyl)₂, or, —S(═O)₂—(C₁-C₆ alkyl); wherein if R¹is an unsubstituted cyclopropyl, if R⁴ is an unsubstituted cyclopropylgroup, or if R⁴ is a substituted or unsubstituted straight or branchedchain C₁-C₆ alkyl group, then at least one of the following is true: (a)if R⁴ is an unsubstituted cyclopropyl group, then R³ is a group offormula -(heterocyclyl)-Q or R³ is a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q and at least one of R^(3d), R^(3e),R^(3f), or R^(3g) is not —H; (b) if R¹ is an unsubstituted cyclopropyl,then R⁴ is a substituted or unsubstituted monocyclic or bicyclic C₆-C₁₀aryl group, a substituted or unsubstituted monocyclic or bicyclicheteroaryl group with 5 to 10 ring members containing 1, 2, or 3heteroatoms independently selected from N, O, or S, or is a substitutedor unsubstituted monocyclic or bicyclic heterocyclyl group with 5 to 10ring members containing 1, 2, 3, or 4 heteroatoms independently selectedfrom N, O, or S, a monocyclic 3-6 membered cycloalkyl group; or (c) ifR⁴ is a substituted or unsubstituted straight or branched chain C₁-C₆alkyl group, then R³ is a group of formula -(heterocyclyl)-Q or R³ is agroup of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q and at least one ofR^(3d), R^(3e), R^(3f), or R^(3g) is not —H.
 2. The compound of claim 1or the pharmaceutically acceptable salt thereof, the tautomer thereof,the pharmaceutically acceptable salt of the tautomer, the stereoisomerof any of the foregoing, or the mixture thereof, wherein R³ is selectedfrom a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q, or a groupof formula -(heterocyclyl)-Q.
 3. The compound of claim 2 or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof, wherein R³ is a group offormula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q.
 4. The compound of claim 3or the pharmaceutically acceptable salt thereof, the tautomer thereof,the pharmaceutically acceptable salt of the tautomer, the stereoisomerof any of the foregoing, or the mixture thereof, wherein R³ is a groupof formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q and further wherein,R^(3d) and R^(3e) are independently selected from —H, —C₁-C₆ alkyl,—(C₁-C₆ alkyl)-OH, or —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl); and R^(3f) andR^(3g) are independently selected from —H, —F, —C₁-C₆ alkyl, —C₁-C₆haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), or —O—(C₂-C₆ alkenyl). 5-10.(canceled)
 11. The compound of claim 1 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R³ is selected from

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule. 12-13. (canceled)
 14. The compound of claim 1 or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof, wherein R³ is selectedfrom

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule. 15-18. (canceled)
 19. The compound of claim 1 or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof, wherein R³ is selectedfrom

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule.
 20. (canceled)
 21. The compound of claim 1 or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof, wherein Q is selected frompyrimidinyl, pyrazinyl, pyridinyl, or phenyl, any of which may beunsubstituted or substituted with 1, 2, or 3 R^(Q) substituents. 22.(canceled)
 23. The compound of claim 1 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein Q is a monocyclic heteroarylgroup with 5 or 6 ring members containing 1 or 2 heteroatoms selectedfrom N, O, or S and Q is unsubstituted or is substituted with 1 or 2R^(Q) substituents. 24-25. (canceled)
 26. The compound of claim 1 or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof, wherein R^(Q) in eachinstance is independently selected from —F, —Cl, —Br, —CN, —C₁-C₆ alkyl,—C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), or —O—(C₁-C₆ perhaloalkyl).
 27. (canceled)
 28. The compoundof claim 1 or the pharmaceutically acceptable salt thereof, the tautomerthereof, the pharmaceutically acceptable salt of the tautomer, thestereoisomer of any of the foregoing, or the mixture thereof, wherein Qis selected from

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule. 29-34. (canceled)
 35. The compound of claim 1 or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof, wherein R² is —H or isabsent in the compounds of Formula II.
 36. The compound of claim 1 orthe pharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof, wherein R⁴ is a phenyl,pyridinyl, or pyrimidinyl, any of which may be unsubstituted orsubstituted with 1, 2, or 3 R^(4a) substituents.
 37. (canceled)
 38. Thecompound of claim 1 or the pharmaceutically acceptable salt thereof, thetautomer thereof, the pharmaceutically acceptable salt of the tautomer,the stereoisomer of any of the foregoing, or the mixture thereof,wherein R^(4a) is in each instance independently selected from —F, —Br,—CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆alkyl)-OH, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆perhaloalkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl-OH), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl),or —C(═O)N(C₁-C₆ alkyl)₂. 39-40. (canceled)
 41. The compound of claim 1or the pharmaceutically acceptable salt thereof, the stereoisomer of anyof the foregoing, or the mixture thereof, wherein R⁴ is selected from

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule.
 42. (canceled)
 43. The compound of claim 1 or thepharmaceutically acceptable salt thereof, the tautomer thereof, thepharmaceutically acceptable salt of the tautomer, the stereoisomer ofany of the foregoing, or the mixture thereof, wherein R⁴ is a phenyl orpyrimidinyl substituted with 1 or 2 R^(4a) substituents.
 44. Thecompound of claim 43 or the pharmaceutically acceptable salt thereof,the tautomer thereof, the pharmaceutically acceptable salt of thetautomer, the stereoisomer of any of the foregoing, or the mixturethereof, wherein the R^(4a) substituents are —O—(C₁-C₂ alkyl) groups.45. (canceled)
 46. The compound of claim 1 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R¹ is an unsubstitutedmonocyclic C₃-C₈ cycloakyl or is a monocyclic C₃-C₈ cycloakylsubstituted with 1, 2, 3, or 4 R^(1a) substituents.
 47. (canceled) 48.The compound of claim 1 or the pharmaceutically acceptable salt thereof,the tautomer thereof, the pharmaceutically acceptable salt of thetautomer, the stereoisomer of any of the foregoing, or the mixturethereof, wherein R¹ is an unsubstituted C₅-C₈ polycyclic cycloalkyl oris a C₅-C₈ polycyclic cycloalkyl substituted with 1, 2, or 3 R^(1a)substituents.
 49. The compound of claim 1 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, wherein R^(1a) is absent or R^(1a) isindependently selected from —F, —CN, —CH₃, —CF₃, —CHF₂, —CH₂F, —CH₂CHF₂,═CH₂, ═O, —OH, —OCH₃, —OCHF₂, —OCH₂CH₃, or —CH₂OH.
 50. The compound ofclaim 1 or the pharmaceutically acceptable salt thereof, the tautomerthereof, the pharmaceutically acceptable salt of the tautomer, thestereoisomer of any of the foregoing, or the mixture thereof, wherein R¹is selected from

wherein the symbol

when drawn across a bond, indicates the point of attachment to the restof the molecule.
 51. The compound of claim 1, wherein the compound hasthe Formula IA

or is the pharmaceutically acceptable salt thereof, the tautomerthereof, the pharmaceutically acceptable salt of the tautomer, thestereoisomer of any of the foregoing, or the mixture thereof, wherein:R¹ is as defined in claim 1; X is selected from CH or N; Z is selectedfrom CH or N; R^(3d) and R^(3e) are independently selected from —H,—C₁-C₆ alkyl, —(C₁-C₆ alkyl)-OH, or —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl); andR^(3f) and R^(3g) are independently selected from —H, —F, —C₁-C₆ alkyl,—C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ perhaloalkyl), or —O—(C₂-C₆alkenyl). Q is a phenyl group or a monocyclic heteroaryl group with 6ring members containing 1 or 2 N heteroatoms, wherein the phenyl and themonocyclic heteroaryl Q groups are unsubstituted or are substituted with1, 2, or 3 R^(Q) substituent; and R^(Q) is independently selected from—F, —Cl, —Br, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl,—O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —(C₁-C₆alkyl)-NH₂ or —S(═O)₂—(C₁-C₆ alkyl). 52-55. (canceled)
 56. The compoundof claim 1, wherein the compound has the Formula IB

or is the pharmaceutically acceptable salt thereof, the tautomerthereof, the pharmaceutically acceptable salt of the tautomer, thestereoisomer of any of the foregoing, or the mixture thereof, wherein:R¹ is as defined in claim 1; X is selected from CH or N; Z is selectedfrom CH or N; R^(3h) is independently selected from —OH, or —O—(C₁-C₆alkyl); the subscript p is selected from 0, 1, 2, or 3; Q is a phenylgroup or a monocyclic heteroaryl group with 6 ring members containing 1or 2 N heteroatoms, wherein the phenyl and the monocyclic heteroaryl Qgroups are unsubstituted or are substituted with 1, 2, or 3 R^(Q)substituent; and R^(Q) is independently selected from —F, —Cl, —Br, —CN,—C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —O—(C₁-C₆ alkyl),—O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —(C₁-C₆ alkyl)-NH₂ or—S(═O)₂—(C₁-C₆ alkyl). 57-68. (canceled)
 69. A pharmaceuticalcomposition, comprising the compound of claim 1 or the pharmaceuticallyacceptable salt thereof, the tautomer thereof, the pharmaceuticallyacceptable salt of the tautomer, the stereoisomer of any of theforegoing, or the mixture thereof, and at least one pharmaceuticallyacceptable excipient.
 70. A pharmaceutical composition, comprising thecompound of claim 1 or the pharmaceutically acceptable salt thereof andat least one pharmaceutically acceptable excipient. 71-72. (canceled)73. The pharmaceutical composition of claim 70, further comprising atherapeutic agent selected from an α-blocker, a β-blocker, anangiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptorblocker (ARB), a calcium channel blocker, a diuretic, an inhibitor ofthe funny current, a myosin activator, or a neutral endopeptidase (NEP)inhibitor.
 74. (canceled)
 75. A method of treating a cardiovascularcondition, the method comprising: administering to a subject aneffective amount of the compound of claim 1 or the pharmaceuticallyacceptable salt thereof, the stereoisomer of any of the foregoing, orthe mixture thereof.
 76. The method of claim 75, wherein thecardiovascular condition is heart failure.
 77. The method of claim 75,wherein the cardiovascular condition is heart failure with reducedejection fraction.
 78. The method of claim 75, wherein thecardiovascular condition is heart failure with preserved ejectionfraction. 79-86. (canceled)
 87. The method of claim 75, wherein themethod includes administering at least one additional therapeutic agentto the subject, wherein the additional therapeutic agent is selectedfrom an α-blocker, a β-blocker, an angiotensin converting enzyme (ACE)inhibitor, an angiotensin-receptor blocker (ARB), a calcium channelblocker, a diuretic, an inhibitor of the funny current, a myosinactivator, or a neutral endopeptidase (NEP) inhibitor. 88-116.(canceled)
 117. A compound of Formula V, a salt thereof, a tautomerthereof, or a salt of the tautomer:

wherein: R¹ is an unsubstituted monocyclic C₃-C₈ cycloalkyl, anunsubstituted C₅-C₈ polycyclic cycloalkyl, an unsubstituted monocyclicC₄-C₈ cycloalkenyl, a monocyclic C₃-C₈ cycloalkyl substituted with 1, 2,3, or 4 R^(1a) substituents, a C₅-C₈ polycyclic cycloalkyl substitutedwith 1, 2, or 3 R^(1a) substituents, or a monocyclic C₄-C₈ cycloalkenylsubstituted with 1, 2, or 3 R^(1a) substituents; R^(1a) in each instanceis independently selected from —F, —Cl, —Br, —I, —CN, —OH, ═O, —O—(C₁-C₆alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₁-C₆ alkyl,—C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —C₂-C₄ alkenyl, ═CH₂, ═CH—(C₁-C₆alkyl), —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆haloalkyl)-OH, —(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆perhaloalkyl)-OH, —(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH,—O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH,—O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂,—NHS(═O)₂—(C₁-C₆ alkyl), —S(═O)₂—(C₁-C₆ alkyl), a phenyl group, or amonocyclic heteroaryl group with 5 or 6 ring members containing 1, 2, or3 heteroatoms independently selected from N, O, or S, wherein the R^(1a)phenyl and R^(1a) heteroaryl groups are unsubstituted or are substitutedwith 1, 2, or 3, R^(1a′) substituents; and further wherein two R^(1a)groups on a single carbon atom of a monocyclic C₃-C₈ cycloalkyl R¹ groupmay join together with the carbon atom to which they are attached toform a heterocyclic ring having 3 to 6 members of which 1 or 2 areheteroatoms independently selected from O, N, and S; R^(1a′) is in eachinstance, independently selected from —F, —Cl, —Br, —I, —CN, —OH,O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₁-C₆alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —C₂-C₄ alkenyl, —(C₁-C₆alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)-OH,—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ perhaloalkyl)-OH, —(C₁-C₆perhaloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,—C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂,—C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —NHS(═O)₂—(C₁-C₆ alkyl),or —S(═O)₂₋(C₁-C₆ alkyl); R³ is selected from a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q, a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—C(═O)-Q a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—CH(OH)-Q, a group of formula—(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—(CR^(3f)R^(3g))-Q, a group of formula—(C₃-C₈ cycloalkyl)-Q, or a group of formula -(heterocyclyl)-Q, whereinthe heterocyclyl of the -(heterocyclyl)-Q group has 5 to 7 ring membersof which 1, 2, or 3 are heteroatoms independently selected from N, O, orS and is unsubstituted or is substituted with 1, 2, or 3 R^(3h)substituents, and further wherein the C₃-C₈ cycloalkyl of the —(C₃-C₈cycloalkyl)-Q group is unsubstituted or is substituted with 1 or 2R^(3h) substituents; R^(3d) and R^(3e) are independently selected from—H, —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl,—OH, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl)-phenyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl),—O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆alkyl), —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂; R^(3f) and R^(3g)are independently selected from —H, —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆ alkyl)-OH, —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl),—O—(C₁-C₆ perhaloalkyl), —O—(C₂-C₆ alkenyl), —O—(C₁-C₆ alkyl)-OH,—O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆alkyl)₂; R^(3h) in each instance is independently selected from —F, —Cl,—CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)—(C₃-C₆ cycloalkyl),—C(═O)—O—(C₁-C₆ alkyl), oxo, or —C(═O)-(heterocyclyl), wherein theheterocyclyl group of the R^(h)—C(═O)-(heterocyclyl) has 5 or 6 ringmembers of which 1 or 2 are heteroatoms independently selected from N,or S or has 3 or 4 ring members of which 1 is a heteroatom selected fromN, O, or S; Q is a monocyclic or bicyclic C₆-C₁₀ aryl group, amonocyclic or bicyclic heteroaryl group with 5 to 10 ring memberscontaining 1, 2, or 3 heteroatoms independently selected from N, O, orS, a C₃-C₈ cycloalkyl group, a 3 to 10 membered heterocyclyl groupcontaining 1, 2, or 3 heteroatoms independently selected from N, O, orS, wherein the C₆-C₀ aryl, the heteroaryl, the cycloalkyl, and theheterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3,or 4 R^(Q) substituents; and further wherein the Q heterocyclyl groupmay additionally be substituted with 1 or 2 oxo substituents, and the Qheteroaryl group may include an N-oxide if the heteroaryl includes a Nheteroatom; R^(Q) in each instance is independently selected from —F,—Cl, —Br, —I, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl,—C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)₂, —NHC(═O)(C₁-C₆ alkyl), —C(═O)—(C₁-C₆ alkyl), —C(═O)OH,—C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆alkyl)₂, —S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-OH, —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-NH₂, —(C₁-C₆ alkyl)-NH—(C₁-C₆alkyl), —(C₁-C₆ alkyl)-N—(C₁-C₆ alkyl)₂, phenyl, a heterocyclyl group, a—(C₁-C₆ alkyl)heterocyclyl group, or a heteroaryl group with 5 or 6 ringmembers and 1, 2, or 3, heteroatoms independently selected from N, O, orS, wherein the heterocyclyl groups of the R^(Q) heterocyclyl and —(C₁-C₆alkyl)heterocyclyl groups have 3 to 6 ring members of which 1 or 2 areheteroatoms independently selected from N, O, or S, and further whereinthe heterocyclyl and the heterocyclyl of the —(C₁-C₆ alkyl)heterocyclylR^(Q) groups may be further substituted with one or two oxo substituentsand a substituent selected from —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₆alkyl, or —C(═O)—(C₁-C₆ alkyl); R⁴ is selected from a monocyclic orbicyclic C₆-C₀ aryl group, a monocyclic or bicyclic heteroaryl groupwith 5 to 10 ring members containing 1, 2, or 3 heteroatomsindependently selected from N, O, or S, a monocyclic or bicyclicheterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4heteroatoms independently selected from N, O, or S, a monocyclic 3-6membered cycloalkyl group, or a straight or branched chain C₁-C₆ alkylgroup, wherein the C₆-C₁₀ aryl, the heteroaryl, the heterocyclyl, andthe cycloalkyl R⁴ group are unsubstituted or are substituted with 1, 2,3, or 4 R^(4a) substituents, and further wherein the straight orbranched chain C₁-C₆ alkyl R⁴ group is unsubstituted or is substitutedwith 1, 2, or 3 R^(4b) substituents; R^(4a) in each instance isindependently selected from —F, —Cl, —Br, —I, —CN, —C₁-C₆ alkyl, —C₁-C₆haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆alkyl)-O—(C₁-C₆ alkyl), —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl),—O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,NH(C₁-C₆ alkyl-OH), —N(C₁-C₆ alkyl-OH)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH,—C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆alkyl)₂, phenyl, —S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-heterocyclyl, orheterocyclyl wherein the heterocyclyl of the —(C₁-C₆ alkyl)-heterocyclyland heterocyclyl R^(4a) groups is a 3-6 membered ring comprising 1 or 2heteroatoms independently selected from N, O, or S, and is unsaturatedor partially unsaturated and is optionally substituted with 1 or 2 oxosubstituents, and further wherein the heterocyclyl of the R⁴ group maybe further substituted with 1 oxo substituent; and R^(4b) in eachinstance is selected from —F, —Cl, —Br, —I, —CN, —OH, —O—(C₁-C₆ alkyl),—O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆ alkyl-OH)₂, —C(═O)—(C₁-C₆alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆alkyl), —C(═O)N(C₁-C₆ alkyl)₂, or, —S(═O)₂—(C₁-C₆ alkyl). 118-136.(canceled)